In this article, we focus on estimating the joint relationship between structural magnetic resonance imaging (sMRI) gray matter (GM), and multiple functional MRI (fMRI) intrinsic connectivity networks (ICNs). To achieve this, we propose a multilink joint independent component analysis (ml‐jICA) method using the same core algorithm as jICA. To relax the jICA assumption, we propose another extension called parallel multilink jICA (pml‐jICA) that allows for a more balanced weight distribution over ml‐jICA/jICA. We assume a shared mixing matrix for both the sMRI and fMRI modalities, while allowing for different mixing matrices linking the sMRI data to the different ICNs. We introduce the model and then apply this approach to study the differences in resting fMRI and sMRI data from patients with Alzheimer's disease (AD) versus controls. The results of the pml‐jICA yield significant differences with large effect sizes that include regions in overlapping portions of default mode network, and also hippocampus and thalamus. Importantly, we identify two joint components with partially overlapping regions which show opposite effects for AD versus controls, but were able to be separated due to being linked to distinct functional and structural patterns. This highlights the unique strength of our approach and multimodal fusion approaches generally in revealing potentially biomarkers of brain disorders that would likely be missed by a unimodal approach. These results represent the first work linking multiple fMRI ICNs to GM components within a multimodal data fusion model and challenges the typical view that brain structure is more sensitive to AD than fMRI.
- NSF-PAR ID:
- 10324578
- Date Published:
- Journal Name:
- BMC Medical Genomics
- Volume:
- 15
- Issue:
- S2
- ISSN:
- 1755-8794
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objective . Spontaneous fluctuations of cerebral hemodynamics measured by functional magnetic resonance imaging (fMRI) are widely used to study the network organization of the brain. The temporal correlations among the ultra-slow, <0.1 Hz fluctuations across the brain regions are interpreted as functional connectivity maps and used for diagnostics of neurological disorders. However, despite the interest narrowed in the ultra-slow fluctuations, hemodynamic activity that exists beyond the ultra-slow frequency range could contribute to the functional connectivity, which remains unclear.Approach . In the present study, we have measured the brain-wide hemodynamics in the human participants with functional near-infrared spectroscopy (fNIRS) in a whole-head, cap-based and high-density montage at a sampling rate of 6.25 Hz. In addition, we have acquired resting state fMRI scans in the same group of participants for cross-modal evaluation of the connectivity maps. Then fNIRS data were deliberately down-sampled to a typical fMRI sampling rate of ∼0.5 Hz and the resulted differential connectivity maps were subject to a k-means clustering.Main results . Our diffuse optical topographical analysis of fNIRS data have revealed a default mode network (DMN) in the spontaneous deoxygenated and oxygenated hemoglobin changes, which remarkably resemble the same fMRI network derived from participants. Moreover, we have shown that the aliased activities in the down-sampled optical signals have altered the connectivity patterns, resulting in a network organization of aliased functional connectivity in the cerebral hemodynamics.Significance. The results have for the first time demonstrated that fNIRS as a broadly accessible modality can image the resting-state functional connectivity in the posterior midline, prefrontal and parietal structures of the DMN in the human brain, in a consistent pattern with fMRI. Further empowered by the fast sampling rate of fNIRS, our findings suggest the presence of aliased connectivity in the current understanding of the human brain organization. -
Abstract Background Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer’s disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect on the development of AD. However, this remains a challenging task due to the tissue-specific nature of transcriptomic and proteomic data and the limited availability of brain tissue.In this paper, instead of using coupled transcriptomic data, we performed an integrative analysis of existing GWAS findings and expression quantitative trait loci (eQTL) results from AD-related brain regions to estimate the transcriptomic alterations in AD brain. Results We used summary-based mendelian randomization method along with heterogeneity in dependent instruments method and were able to identify 32 genes with potential altered levels in temporal cortex region. Among these, 10 of them were further validated using real gene expression data collected from temporal cortex region, and 19 SNPs from NECTIN and TOMM40 genes were found associated with multiple temporal cortex imaging phenotype. Conclusion Significant pathways from enriched gene networks included neutrophil degranulation, Cell surface interactions at the vascular wall, and Regulation of TP53 activity which are still relatively under explored in Alzheimer’s Disease while also encouraging a necessity to bind further trans-eQTL effects into this integrative analysis.more » « less
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Abstract Convergent research identifies a general factor (“P factor”) that confers transdiagnostic risk for psychopathology. Large-scale networks are key organizational units of the human brain. However, studies of altered network connectivity patterns associated with the P factor are limited, especially in early adolescence when most mental disorders are first emerging. We studied 11,875 9- and 10-year olds from the Adolescent Brain and Cognitive Development (ABCD) study, of whom 6593 had high-quality resting-state scans. Network contingency analysis was used to identify altered interconnections associated with the P factor among 16 large-scale networks. These connectivity changes were then further characterized with quadrant analysis that quantified the directionality of P factor effects in relation to neurotypical patterns of positive versus negative connectivity across connections. The results showed that the P factor was associated with altered connectivity across 28 network cells (i.e., sets of connections linking pairs of networks);
p PERMUTATIONvalues < 0.05 FDR-corrected for multiple comparisons. Higher P factor scores were associated with hypoconnectivity within default network and hyperconnectivity between default network and multiple control networks. Among connections within these 28 significant cells, the P factor was predominantly associated with “attenuating” effects (67%;p PERMUTATION < 0.0002), i.e., reduced connectivity at neurotypically positive connections and increased connectivity at neurotypically negative connections. These results demonstrate that the general factor of psychopathology produces attenuating changes across multiple networks including default network, involved in spontaneous responses, and control networks involved in cognitive control. Moreover, they clarify mechanisms of transdiagnostic risk for psychopathology and invite further research into developmental causes of distributed attenuated connectivity. -
INTRODUCTION A brainwide, synaptic-resolution connectivity map—a connectome—is essential for understanding how the brain generates behavior. However because of technological constraints imaging entire brains with electron microscopy (EM) and reconstructing circuits from such datasets has been challenging. To date, complete connectomes have been mapped for only three organisms, each with several hundred brain neurons: the nematode C. elegans , the larva of the sea squirt Ciona intestinalis , and of the marine annelid Platynereis dumerilii . Synapse-resolution circuit diagrams of larger brains, such as insects, fish, and mammals, have been approached by considering select subregions in isolation. However, neural computations span spatially dispersed but interconnected brain regions, and understanding any one computation requires the complete brain connectome with all its inputs and outputs. RATIONALE We therefore generated a connectome of an entire brain of a small insect, the larva of the fruit fly, Drosophila melanogaster. This animal displays a rich behavioral repertoire, including learning, value computation, and action selection, and shares homologous brain structures with adult Drosophila and larger insects. Powerful genetic tools are available for selective manipulation or recording of individual neuron types. In this tractable model system, hypotheses about the functional roles of specific neurons and circuit motifs revealed by the connectome can therefore be readily tested. RESULTS The complete synaptic-resolution connectome of the Drosophila larval brain comprises 3016 neurons and 548,000 synapses. We performed a detailed analysis of the brain circuit architecture, including connection and neuron types, network hubs, and circuit motifs. Most of the brain’s in-out hubs (73%) were postsynaptic to the learning center or presynaptic to the dopaminergic neurons that drive learning. We used graph spectral embedding to hierarchically cluster neurons based on synaptic connectivity into 93 neuron types, which were internally consistent based on other features, such as morphology and function. We developed an algorithm to track brainwide signal propagation across polysynaptic pathways and analyzed feedforward (from sensory to output) and feedback pathways, multisensory integration, and cross-hemisphere interactions. We found extensive multisensory integration throughout the brain and multiple interconnected pathways of varying depths from sensory neurons to output neurons forming a distributed processing network. The brain had a highly recurrent architecture, with 41% of neurons receiving long-range recurrent input. However, recurrence was not evenly distributed and was especially high in areas implicated in learning and action selection. Dopaminergic neurons that drive learning are amongst the most recurrent neurons in the brain. Many contralateral neurons, which projected across brain hemispheres, were in-out hubs and synapsed onto each other, facilitating extensive interhemispheric communication. We also analyzed interactions between the brain and nerve cord. We found that descending neurons targeted a small fraction of premotor elements that could play important roles in switching between locomotor states. A subset of descending neurons targeted low-order post-sensory interneurons likely modulating sensory processing. CONCLUSION The complete brain connectome of the Drosophila larva will be a lasting reference study, providing a basis for a multitude of theoretical and experimental studies of brain function. The approach and computational tools generated in this study will facilitate the analysis of future connectomes. Although the details of brain organization differ across the animal kingdom, many circuit architectures are conserved. As more brain connectomes of other organisms are mapped in the future, comparisons between them will reveal both common and therefore potentially optimal circuit architectures, as well as the idiosyncratic ones that underlie behavioral differences between organisms. Some of the architectural features observed in the Drosophila larval brain, including multilayer shortcuts and prominent nested recurrent loops, are found in state-of-the-art artificial neural networks, where they can compensate for a lack of network depth and support arbitrary, task-dependent computations. Such features could therefore increase the brain’s computational capacity, overcoming physiological constraints on the number of neurons. Future analysis of similarities and differences between brains and artificial neural networks may help in understanding brain computational principles and perhaps inspire new machine learning architectures. The connectome of the Drosophila larval brain. The morphologies of all brain neurons, reconstructed from a synapse-resolution EM volume, and the synaptic connectivity matrix of an entire brain. This connectivity information was used to hierarchically cluster all brains into 93 cell types, which were internally consistent based on morphology and known function.more » « less
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1186/s12920-022-01244-6
