Tian Ge

Depression uncouples brain hate circuit

It is increasingly recognized that we need a better understanding of how mental disorders such as depression alter the brains functional connections to improve both early diagnosis and therapy. A new holistic approach has been used to investigate functional connectivity changes in the brains of patients suffering from major depression using resting-state functional magnetic resonance imaging (fMRI) data. A canonical template of connectivity in 90 different brain regions was constructed from healthy control subjects and this identified a six-community structure with each network corresponding to a different functional system. This template was compared with functional networks derived from fMRI scans of both first-episode and longer-term, drug resistant, patients suffering from severe depression. The greatest change in both groups of depressed patients was uncoupling of the so-called ‘hate circuit’ involving the superior frontal gyrus, insula and putamen. Other major changes occurred in circuits related to risk and action responses, reward and emotion, attention and memory processing. A voxel-based morphometry analysis was also carried out but this revealed no evidence in the depressed patients for altered gray or white matter densities in the regions showing altered functional connectivity. This is the first evidence for the involvement of the ‘hate circuit’ in depression and suggests a potential reappraisal of the key neural circuitry involved. We have hypothesized that this may reflect reduced cognitive control over negative feelings toward both self and others.

Genetics of the connectome

Connectome genetics attempts to discover how genetic factors affect brain connectivity. Here we review a variety of genetic analysis methods--such as genome-wide association studies (GWAS), linkage and candidate gene studies--that have been fruitfully adapted to imaging data to implicate specific variants in the genome for brain-related traits. Studies that emphasized the genetic influences on brain connectivity. Some of these analyses of brain integrity and connectivity using diffusion MRI, and others have mapped genetic effects on functional networks using resting state functional MRI. Connectome-wide genome-wide scans have also been conducted, and we review the multivariate methods required to handle the extremely high dimension of the genomic and network data. We also review some consortium efforts, such as ENIGMA, that offer the power to detect robust common genetic associations using phenotypic harmonization procedures and meta-analysis. Current work on connectome genetics is advancing on many fronts and promises to shed light on how disease risk genes affect the brain. It is already discovering new genetic loci and even entire genetic networks that affect brain organization and connectivity.

Increasing power for voxel-wise genome-wide association studies: The random field theory, least square kernel machines and fast permutation procedures

Imaging traits are thought to have more direct links to genetic variation than diagnostic measures based on cognitive or clinical assessments and provide a powerful substrate to examine the influence of genetics on human brains. Although imaging genetics has attracted growing attention and interest, most brain-wide genome-wide association studies focus on voxel-wise single-locus approaches, without taking advantage of the spatial information in images or combining the effect of multiple genetic variants. In this paper we present a fast implementation of voxel- and cluster-wise inferences based on the random field theory to fully use the spatial information in images. The approach is combined with a multi-locus model based on least square kernel machines to associate the joint effect of several single nucleotide polymorphisms (SNP) with imaging traits. A fast permutation procedure is also proposed which significantly reduces the number of permutations needed relative to the standard empirical method and provides accurate small p-value estimates based on parametric tail approximation. We explored the relation between 448,294 single nucleotide polymorphisms and 18,043 genes in 31,662 voxels of the entire brain across 740 elderly subjects from the Alzheimers disease neuroimaging initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. We find method to be more sensitive compared with voxel-wise single-locus approaches. A number of genes were identified as having significant associations with volumetric changes. The most associated gene was GRIN2B, which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit and affects both the parietal and temporal lobes in human brains. Its role in Alzheimers disease has been widely acknowledged and studied, suggesting the validity of the approach. The various advantages over existing approaches indicate a great potential offered by this novel framework to detect genetic influences on human brains.

Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain

Significance The human cerebral cortex is patterned with distributed networks that connect disproportionately enlarged association zones across the frontal, temporal, and parietal lobes. We asked herein whether the expansion of the cortical surface, with the concomitant emergence of long-range connectivity networks, might be accompanied by changes to the underlying molecular architecture. We focused on the supragranular layers of the cortex, where most corticocortical connections originate. Genes that are enriched in supragranular layers in the human cerebral cortex relative to mouse are expressed in a topography that reflects broad cortical classes (sensory/motor, paralimbic, associational) and their associated network properties. Molecular innovations of upper cortical layers may be an important component in the evolution of increased long-range corticocortical projections. The human brain is patterned with disproportionately large, distributed cerebral networks that connect multiple association zones in the frontal, temporal, and parietal lobes. The expansion of the cortical surface, along with the emergence of long-range connectivity networks, may be reflected in changes to the underlying molecular architecture. Using the Allen Institute’s human brain transcriptional atlas, we demonstrate that genes particularly enriched in supragranular layers of the human cerebral cortex relative to mouse distinguish major cortical classes. The topography of transcriptional expression reflects large-scale brain network organization consistent with estimates from functional connectivity MRI and anatomical tracing in nonhuman primates. Microarray expression data for genes preferentially expressed in human upper layers (II/III), but enriched only in lower layers (V/VI) of mouse, were cross-correlated to identify molecular profiles across the cerebral cortex of postmortem human brains (n = 6). Unimodal sensory and motor zones have similar molecular profiles, despite being distributed across the cortical mantle. Sensory/motor profiles were anticorrelated with paralimbic and certain distributed association network profiles. Tests of alternative gene sets did not consistently distinguish sensory and motor regions from paralimbic and association regions: (i) genes enriched in supragranular layers in both humans and mice, (ii) genes cortically enriched in humans relative to nonhuman primates, (iii) genes related to connectivity in rodents, (iv) genes associated with human and mouse connectivity, and (v) 1,454 gene sets curated from known gene ontologies. Molecular innovations of upper cortical layers may be an important component in the evolution of long-range corticocortical projections.

Componential Granger causality, and its application to identifying the source and mechanisms of the top–down biased activation that controls attention to affective vs sensory processing

We describe a new measure of Granger causality, componential Granger causality, and show how it can be applied to the identification of the directionality of influences between brain areas with functional neuroimaging data. Componential Granger causality measures the effect of y on x, but allows interaction effects between y and x to be measured. In addition, the terms in componential Granger causality sum to 1, allowing causal effects to be directly compared between systems. We show using componential Granger causality analysis applied to an fMRI investigation that there is a top-down attentional effect from the anterior dorsolateral prefrontal cortex to the orbitofrontal cortex when attention is paid to the pleasantness of a taste, and that this effect depends on the activity in the orbitofrontal cortex as shown by the interaction term. Correspondingly there is a top-down attentional effect from the posterior dorsolateral prefrontal cortex to the insular primary taste cortex when attention is paid to the intensity of a taste, and this effect depends on the activity of the insular primary taste cortex as shown by the interaction term. Componential Granger causality thus not only can reveal the directionality of effects between areas (and these can be bidirectional), but also allows the mechanisms to be understood in terms of whether the causal influence of one system on another depends on the state of the system being causally influenced. Componential Granger causality measures the full effects of second order statistics by including variance and covariance effects between each time series, thus allowing interaction effects to be measured, and also provides a systematic framework within which to measure the effects of cross, self, and noise contributions to causality. The findings reveal some of the mechanisms involved in a biased activation theory of selective attention.

Massively expedited genome-wide heritability analysis (MEGHA)

Significance Practical tools for high-dimensional heritability-based screening are invaluable for prioritizing phenotypes for genetic studies with the dramatic expansion of available phenotypic data. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Alternative methods based on whole-genome data from unrelated individuals exist but are computationally expensive. Here we present a novel, fast, and accurate statistical method for massively expedited genome-wide heritability analysis, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. We apply our method to large-scale heritability analyses of brain imaging measurements and demonstrate its potential for facilitating phenome-wide analyses and characterizing the genetic architecture of complex traits. The discovery and prioritization of heritable phenotypes is a computational challenge in a variety of settings, including neuroimaging genetics and analyses of the vast phenotypic repositories in electronic health record systems and population-based biobanks. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Genome-wide complex trait analysis is an alternative tool to compute heritability estimates from unrelated individuals, using genome-wide data that are increasingly ubiquitous, but is computationally demanding and becomes difficult to apply in evaluating very large numbers of phenotypes. Here we present a fast and accurate statistical method for high-dimensional heritability analysis using genome-wide SNP data from unrelated individuals, termed massively expedited genome-wide heritability analysis (MEGHA) and accompanying nonparametric sampling techniques that enable flexible inferences for arbitrary statistics of interest. MEGHA produces estimates and significance measures of heritability with several orders of magnitude less computational time than existing methods, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. As a demonstration of application, we conducted heritability analyses on global and local morphometric measurements derived from brain structural MRI scans, using genome-wide SNP data from 1,320 unrelated young healthy adults of non-Hispanic European ancestry. We also computed surface maps of heritability for cortical thickness measures and empirically localized cortical regions where thickness measures were significantly heritable. Our analyses demonstrate the unique capability of MEGHA for large-scale heritability-based screening and high-dimensional heritability profile construction.

A novel extended Granger Causal Model approach demonstrates brain hemispheric differences during face recognition learning.

Two main approaches in exploring causal relationships in biological systems using time-series data are the application of Dynamic Causal model (DCM) and Granger Causal model (GCM). These have been extensively applied to brain imaging data and are also readily applicable to a wide range of temporal changes involving genes, proteins or metabolic pathways. However, these two approaches have always been considered to be radically different from each other and therefore used independently. Here we present a novel approach which is an extension of Granger Causal model and also shares the features of the bilinear approximation of Dynamic Causal model. We have first tested the efficacy of the extended GCM by applying it extensively in toy models in both time and frequency domains and then applied it to local field potential recording data collected from in vivo multi-electrode array experiments. We demonstrate face discrimination learning-induced changes in inter- and intra-hemispheric connectivity and in the hemispheric predominance of theta and gamma frequency oscillations in sheep inferotemporal cortex. The results provide the first evidence for connectivity changes between and within left and right inferotemporal cortexes as a result of face recognition learning.

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention.

Phenome-wide heritability analysis of the UK Biobank

Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenome-wide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability.

Heritability analysis with repeat measurements and its application to resting-state functional connectivity

Significance Heritability is a fundamental metric in population genetics. Existing heritability models lump together stable effects (e.g., due to the subject’s unique environment) and transient effects, such as measurement error. This can result in misleading assessments when comparing the heritability of traits that exhibit different levels of reliability. This paper presents a heritability estimation strategy that can account for transient intrasubject variation using repeat measurements. Using the proposed method, we show that the stable components of functional connectivity within and across well-established large-scale brain networks can be considerably heritable. With the explosive expansion of genomics, health informatics, and digital phenotyping technologies, the proposed model will be significant in dissecting the genetic basis of a wide range of informative but noisy phenotypes. Heritability, defined as the proportion of phenotypic variation attributable to genetic variation, provides important information about the genetic basis of a trait. Existing heritability analysis methods do not discriminate between stable effects (e.g., due to the subject’s unique environment) and transient effects, such as measurement error. This can lead to misleading assessments, particularly when comparing the heritability of traits that exhibit different levels of reliability. Here, we present a linear mixed effects model to conduct heritability analyses that explicitly accounts for intrasubject fluctuations (e.g., due to measurement noise or biological transients) using repeat measurements. We apply the proposed strategy to the analysis of resting-state fMRI measurements—a prototypic data modality that exhibits variable levels of test–retest reliability across space. Our results reveal that the stable components of functional connectivity within and across well-established large-scale brain networks can be considerably heritable. Furthermore, we demonstrate that dissociating intra- and intersubject variation can reveal genetic influence on a phenotype that is not fully captured by conventional heritability analyses.