Biology subjects

Parker, D.

Publications and source records attributed to Parker, D..

33 records · Page 2Linked to original sources

bioRxiv2022

Analysis of structural network topology alterations in autism and its relationship with autism severity

Autism Spectrum Disorder (ASD) is a public health concern ranging along a continuum of severity. The neurobiological motives behind ASD have been widely explored with reports about aberrant brain anatomy and functional connectivity. However, research on the underlying structural connectivity alterations is limited. We propose the application of a novel connectomic measure called Network Normality Score (NNS) to identify brain abnormalities and quantity topological dissimilarities in individuals with ASD. We show that the network topology of structural connectivity is altered in ASD brains relative to healthy controls at the global and system levels. We demonstrate that structural connectivity differences are more pronounced in certain subnetworks. Finally, we quantify the association between network similarity and behavioral autism severity to show the efficacy of NNS as a neuroimaging measure.

neuroscience↗

bioRxiv2022

Triggered functional dynamics of AsLOV2 by time-resolved electron paramagnetic resonance at high magnetic fields

We present time-resolved Gd-Gd electron paramagnetic resonance (TiGGER) at 240 GHz for tracking inter-residue distances during a proteins mechanical cycle in the solution state. TiGGER makes use of Gd-sTPATCN as spin labels, whose favorable qualities include a spin-7/2 EPR-active center, short linker, narrow intrinsic linewidth, and virtually no anisotropy at high fields (8.6 T) when compared to nitroxide spin labels. Using TiGGER, we determined that upon light activation, the C-terminus and N-terminus of AsLOV2 separate in less than 1 s and relax back to equilibrium with a time constant of approximately 60 s. TiGGER revealed that the light-activated long-range mechanical motion is slowed in the Q513A variant of AsLOV2 and is correlated to the similarly slowed relaxation of the optically excited chromophore as described in recent literature. TiGGER has the potential to valuably complement existing methods for the study of triggered functional dynamics in proteins.

biophysics↗

bioRxiv2021

The functional properties of synapses made by regenerated axons across spinal cord lesion sites

While the anatomical properties of regenerated axons across spinal cord lesion sites have been studied extensively, little is known of how the functional properties of regenerated synapses compare to those in unlesioned animals. This comparison has been performed here in the lamprey, a model system for spinal injury research, in which functional locomotor recovery after spinal cord lesions is associated with axonal regeneration across the lesion site. Regenerated synapses below the lesion site did not differ to synapses from unlesioned axons with respect to the amplitude and duration of single excitatory postsynaptic potentials (EPSPs). They also showed the same activity-dependent depression over spike trains. However, regenerated synapses did differ to unlesioned synapses as the estimated number of synaptic vesicles was greater and there was evidence for an increased postsynaptic quantal amplitude. For axons above the lesion site, the amplitude and duration of single synaptic inputs also did not differ significantly to unlesioned animals. However, in this case there was evidence of a reduction in release probability and inputs facilitated rather that depressed over spike trains. Synaptic inputs from single regenerated axons below the lesion site thus do not increase in amplitude to compensate for the reduced number of descending axons after functional recovery. However, the postsynaptic input is maintained at the unlesioned level using different synaptic properties. Conversely, the facilitation from the same initial amplitude above the lesion site will make the synaptic input over spike trains functionally stronger. This may help to increase propriospinal activity across the lesion site to compensate for the lesion-induced reduction in supraspinal inputs.

neuroscience↗

bioRxiv2021

Tractography-based targeting of ventral intermediate nucleus: A comparison between conventional stereotactic targeting and diffusion tensor imaging-based targeting

BackgroundThe ventral intermediate (VIM) nucleus of the thalamus is the main target for lesioning using magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) or deep brain stimulation (DBS). Targeting of VIM still depends on standard stereotactic coordinates, which do not account for inter-individual variability. Several approaches have been proposed including visualization of dentato-rubro-thalamic tract (DRTT) using diffusion tensor imaging tractography. ObjectiveTo compare probabilistic tracking of DRTT with deterministic tracking of DRTT and stereotactic coordinates to identify the most appropriate approach to target VIM. MethodsIn this retrospective study, we assessed the VIM targeted using stereotactic coordinates, deterministic and probabilistic tracking of DRTT in 19 patients with essential tremor who underwent DBS with VIM targeted using microelectrode recordings. We subsequently determined the positions of VIM derived from these three approaches and compared with that of DBS lead position using paired sample t-tests. ResultsThe probabilistic tracking of DRTT was significantly anterior to the lead (1.45 {+/-} 1.61 mm (P< 0.0001)), but not in the medial/lateral position (-0.29{+/-}2.42 mm (P=0.50)). Deterministic tracking of DRTT was significantly lateral (2.16 {+/-} 1.94 mm (P< 0.0001)) and anterior to the lead (1.66 {+/-} 2.1 mm (P< 0.0001)). The stereotactic coordinates were significantly lateral (2.41 {+/-} 1.41 mm (P< 0.0001)) and anterior (1.23 {+/-} 0.89 mm (P< 0.0001)) to the lead. ConclusionProbabilistic tracking of DRTT was found to be superior in targeting VIM compared to deterministic tracking and stereotactic coordinates.

neuroscience↗

bioRxiv2021

Connectomic Assessment of Injury Burden and Longitudinal Structural Network Alterations in Moderate-to-severe Traumatic Brain Injury

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been very scarce. In this study, we propose a novel connectomic measure that we call network anomaly score (NAS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients are more heterogeneous and are significantly different than that of healthy controls at 3 months post-injury, where dissimilarity further increases up to 12 months. We also show that NAS captures injury burden as quantified by post-traumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally we compare NAS to major graph theory measures used in TBI literature and demonstrate the superiority of NAS in characterizing the disease.

neuroscience↗

bioRxiv2021

Fine-tuned repression of Drp1 driven mitochondrial fission primes a slow cycling stem/progenitor-like state towards accelerating neoplastic transformation of keratinocytes

The opposing processes of mitochondrial fission and fusion are emerging as crucial regulators of stemness. Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. However, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Here, we demonstrate that only fine-tuned repression of Drp1 establishes a stem/progenitor-like state towards supporting carcinogen driven neoplastic transformation of keratinocytes, while more complete Drp1 repression prevents it. Only fine-tuned Drp1 repression maintains small networks of fused mitochondria to sustain a unique gene-expression profile with elevated stem/progenitor cell functional markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Cells with such a mitochondria-primed state are slow cycling, susceptible to transformation, and when enriched by mild carcinogen exposure sustains elevated self-renewal/proliferation to form less differentiated tumors. Therefore, our data for the first time highlights a goldilocks level of Drp1 repression that supports stem/progenitor state dependent neoplastic transformation.

cell biology↗

bioRxiv2020

Tractography dissection variability: what happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

neuroscience↗

bioRxiv2019

Connectomic consistency: a systematic stability analysisof structural and functional connectivity

Connectomics, the study of brain connectivity, has become an indispensable tool in neuroscientific research as it provides insights into brain organization. Connectomes are generated for different modalities such as using diffusion MRI to capture structural organization of the brain or using functional MRI to elaborate brains functional organization. Understanding links between structural and functional organizations is crucial in explaining how observed behavior emerges from the underlying neurobiological mechanisms. Many studies have investigated how these two organizations relate to each other; however, we still lack a proper understanding on how much variation should be expected on the two modalities, both between people cross-sectionally and within a single person longitudinally. Notably, connectomes of both modalities were shown to have significant differences depending on how they are generated. In this study, for both modalities, we systematically analyzed consistency of connectomes, that is the similarity between connectomes in terms of individual connections between brain regions or in terms of overall network topology. We present a comprehensive study of consistency in structural and resting-state functional connectomes both for a single subject examined longitudinally and across a large cohort of subjects cross-sectionally. We compared connectomes generated by different tracking algorithms, parcellations, edge weighting schemes, and edge pruning techniques. We evaluated consistency both at the levels of individual edges using correlation and at the level of network topology via graph matching accuracy. We also examined consistency of connectomes that are generated using most commonly applied communication schemes. Our results demonstrate varying degrees of consistency for the two modalities, with structural connectomes showing higher consistency than functional connectomes. Moreover, we observed a wide variation in consistency depending on how connectomes are generated. Our study sets a reference point for consistency of connectome types, which is especially important for structure-function coupling studies in evaluating mismatches between modalities.

neuroscience↗

bioRxiv2019

Freewater EstimatoR using iNtErpolated iniTialization (FERNET): Toward Accurate Estimation of Free Water in Peritumoral Region Using Single-Shell Diffusion MRI Data

Characterization of healthy versus pathological tissue is a key concern when modeling tissue microstructure in the peritumoral area, confounded by the presence of free water (e.g., edema). Most methods that model tissue microstructure are either based on advanced acquisition schemes not readily available in the clinic, or are not designed to address the challenge of edema. This underscores the need for a robust free water elimination (FWE) method that estimates free water in pathological tissue but can be used with clinically prevalent single-shell diffusion tensor imaging data. FWE in single-shell data requires the fitting of a bi-compartment model, which is an ill-posed problem. Its solution requires optimization, which relies on an initialization step. We propose a novel initialization approach for FWE, FERNET, which improves the estimation of free water in edematous and infiltrated peritumoral regions, using single-shell diffusion MRI data. The method has been extensively investigated on simulated data and healthy and brain tumor datasets, demonstrating its applicability on clinically acquired data. Additionally, it has been applied to data from brain tumor patients to demonstrate the improvement in tractography in the peritumoral region.

bioengineering↗

bioRxiv2019

Attenuation of Motion Artifacts in fMRI using Discrete Reconstruction of Irregular fMRI Trajectories (DRIFT)

Numerous studies reported motion as the most detrimental source of noise and artifacts in functional magnetic resonance imaging (fMRI). Different approaches have been proposed and used to attenuate the effect of motion on fMRI data, including both prospective and retrospective (post-processing) techniques. However, each type of motion (e.g. translation versus rotation or in-plane versus out-of-plane) has a distinct effect on the MR signal, which is not fully understood nor appropriately modeled in the field. In addition, effects of the same motion can be substantially different depending on when it occurs during the pulse sequence (e.g. RF excitation, gradient encoding, or k-space read-out). Thus, each distinct kind of motion and the time of its occurrence may require a unique approach to be optimally corrected. Therefore, we start with an investigation of the effects of different motions on the MR signal based on the Bloch equation. We then simulate their unique effects with a comprehensive fMRI simulator. Our results indicate that current motion correction methods fail to completely address the motion problem. Retrospective techniques such as spatial realignment can correct for between-volume misalignment, but fail to address within volume contamination and spin-history artifacts. Because of the steady state nature of the fMRI acquisition, spin-history artifacts arising from over/under excitation during slice-selection causes the motion artifacts to contaminate MR signal even after cessation of motion, which makes it challenging to be corrected retrospectively. Prospective motion correction has been proposed to prevent spin-history artifacts, but fails to address motion artifacts during k-space readout. In this article, we propose a novel method to remove these artifacts: Discrete reconstruction of irregular fMRI trajectory (DRIFT). Our method calculates the exact displacement of k-space recording due to motion at each dwell time and retrospectively corrects each slice of the fMRI volume using an inverse nonuniform Fourier transform. We evaluate our proposed methods using simulated data as well as fMRI data collected from a rotating phantom inside a 3T Siemens Prisma scanner. We conclude that a hybrid approach with both prospective and retrospective components are essentially required for optimal removal of motion artifacts from the fMRI data.

neuroscience↗

bioRxiv2019

Mito-SinCe2 Approach to Quantify Relationships between Mitochondrial Dynamics and Energetics status

Mitochondrial dynamics primarily refers to the opposing fission and fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. The details of the bidirectional relationship between mitochondrial dynamics and energetics are unclear as the methods to integrate these mitochondrial aspects are lacking. To study the quantitative relationship between mitochondrial dynamics (fission, fusion, matrix continuity and diameter) and energetics (ATP and redox), we have developed and validated an analytical approach, mito-SinCe2. Application of this approach led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct relationships between mitochondrial energetics and dynamics. Interestingly, fusion and ATP increase linearly with each other only once a certain level of fusion is attained. Moreover, mitochondrial dynamics status changes linearly either with ATP or with redox, but not simultaneously with both. Furthermore, mito-SinCe2 analyses can potentially predict new quantitative features of the opposing fission vs. fusion relationship and classify cells into functional classes based on their mito-SinCe2 states.

cell biology↗

bioRxiv2018

Cerebral amyloid angiopathy and comparative analysis of amyloid-β protein in birds

Senile plaques and cerebral amyloid angiopathy (CAA) are well-documented in various mammals, and several species even exhibit neurofibrillary tangle (NFT). However, we know far less about whether such symptoms are present in birds. Therefore, here we clarified the occurrence and pathogenesis of avian a{beta}-related lesions, analyzing the a{beta} amino-acid sequence across 28 birds at multiple life stages, representing 15 species, 14 genera, and 9 nine families. We also determined the expected a{beta} amino-acid sequence after comparing data from the brains of nine birds (seven species) with publicly available NCBI data. We observed CAA and senile plaque-like deposition only in a female Amazon parrot, estimated to be around 30-40 years old. We identified two A{beta} depositions (40 and 42) in the same location that correspond to A{beta} 6-42. Additionally, we observed severe A{beta} deposition, accompanied by severe hemorrhaging, in blood vessels of the superficial and deep portions of the brain. These lesions were directly related to the cause of death. Of 40 bird species, 36 exhibited type 1 A{beta} amino-acid sequences, similar to humans. Given that all of these birds were old, our results suggest that A{beta} is deposited primarily as CAA as the animals age. This report is the first clinically based description of CAA in birds. Interspecific variation likely exists because we identified species that did not exhibit A{beta} deposition even when the birds are old enough. However, even birds of the same taxonomic status differed in whether they possessed or lacked A{beta} deposition. Thus, other factors besides A{beta} amino-acid sequence could influence this symptom.

pathology↗

bioRxiv2018

Genes involved in the convergent evolution of asexuality in stick insects

Asexual reproduction has evolved repeatedly from sexual ancestors across a wide range of taxa. While the costs and benefits associated with asexuality have received considerable attention, the molecular changes underpinning the evolution of asexual reproduction remain relatively unexplored. In particular, it is completely unknown whether the repeated evolution of asexual phenotypes involves similar molecular changes, as previous studies have focused on changes occurring in single lineages. Here we investigate the extent of convergent gene expression changes across five independent transitions to asexuality in stick insects. We compared gene expression of asexual females to females of close sexual relatives in whole-bodies, reproductive tracts, and legs. We identified a striking amount of convergent gene expression change (up to 8% of genes), greatly exceeding that expected by chance. Convergent changes were also tissue-specific, and most likely driven by selection for functional changes. Genes showing convergent changes in the reproductive tract were associated with meiotic spindle formation and centrosome organization. These genes are particularly interesting as they can influence the production of unreduced eggs, a key barrier to asexual reproduction. Changes in legs and whole-bodies were likely involved in female sexual trait decay, with enrichment in terms such as sperm-storage and pigmentation. By identifying changes occurring across multiple independent transitions to asexuality, our results provide a rare insight into the molecular basis of asexual phenotypes and suggest that the evolutionary path to asexuality is highly constrained, requiring repeated changes to the same key genes.

evolutionary biology↗

bioRxiv2017

Multifactorial Dynamics of White Matter Connectivity During Adolescence

Studying developmental changes in white matter connectivity is critical for understanding neurobiological substrates of cognition, learning, and neuropsychiatric disorders. This becomes especially important during adolescence when a rapid expansion of the behavioral repertoire occurs. Several factors such as brain geometry, genetic expression profiles, and higher level architectural specifications such as the presence of segregated modules have been associated with the observed organization of white matter connections. However, we lack understanding of the extent to which such factors jointly describe the brain network organization, nor have insights into how their contribution changes developmentally. We constructed a multifactorial model of white matter connectivity using Bayesian network analysis and tested it with diffusion imaging data from a large community sample. We investigated contributions of multiple factors in explaining observed connectivity, including architectural specifications, which promote a modular yet integrative organization, and brains geometric and genetic features. Our results demonstrated that the initially dominant geometric and genetic factors become less influential with age, whereas the effect of architectural specifications increases. The identified structural modules are associated with well-known functional systems, and the level of association increases with age. This integrative analysis provides a computational characterization of the normative evolution of structural connectivity during adolescence.

neuroscience↗

bioRxiv2017

Harmonization Of Multi-Site Diffusion Tensor Imaging Data

Diffusion tensor imaging (DTI) is a well-established magnetic resonance imaging (MRI) technique used for studying microstructural changes in the white matter. As with many other imaging modalities, DTI images suffer from technical between-scanner variation that hinders comparisons of images across imaging sites, scanners and over time. Using fractional anisotropy (FA) and mean diffusivity (MD) maps of 205 healthy participants acquired on two different scanners, we show that the DTI measurements are highly site-specific, highlighting the need of correcting for site effects before performing downstream statistical analyses. We first show evidence that combining DTI data from multiple sites, without harmonization, is counter-productive and negatively impacts the inference. Then, we propose and compare several harmonization approaches for DTI data, and show that ComBat, a popular batch-effect correction tool used in genomics, performs best at modeling and removing the unwanted inter-site variability in FA and MD maps. Using age as a biological phenotype of interest, we show that ComBat both preserves biological variability and removes the unwanted variation introduced by site. Finally, we assess the different harmonization methods in the presence of different levels of confounding between site and age, in addition to test robustness to small sample size studies.

neuroscience↗