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Peterson, K. L.

Publications and source records attributed to Peterson, K. L..

4 recordsLinked to original sources

Hierarchical and non-hierarchical network flows generate complementary representational dynamics in human visual cortex

Hierarchy is considered a fundamental organizing principle of visual cortex, but its functional implications remain debated given the presence of direct (non-hierarchical) connections. Building on recent advances in measuring direct region-to-region functional connectivity in the human brain, and in using that connectivity (rather than, e.g., visual classification training) to construct deep neural network models, we tested the hypothesis that hierarchical and direct connectivity pathways make distinct contributions to the generation of visual functionality. Detailed measurement of visual functionality, connectivity, and their interaction was achieved using 7T MRI and empirical neural network (ENN) models parameterized by empirical connectivity estimates. The classic V1 to V4 hierarchy was recovered in terms of (i) network distance from V1 along the human brains direct region-to-region resting-state functional connectome and (ii) on-task representational transformation distance (visual representation dissimilarity) from V1. In silico ENN lesion experiments revealed that hierarchical pathways (V1{leftrightarrow}V2{leftrightarrow}V3{leftrightarrow}V4) reduce the dimensionality of neural representations relative to more rapid and high-dimensional representational contributions from direct pathways (e.g., V1{leftrightarrow}V4). These findings reveal distinct but complementary roles of hierarchical and direct pathways in generating cortical functionality. Significance StatementHierarchy is a foundational organizing principle of cortex, yet its functional consequences remain unclear because of direct, non-hierarchical connections. The visual system, often portrayed as the clearest example of cortical hierarchy, provides a testbed for dissociating hierarchical and non-hierarchical contributions. Using high-resolution 7T MRI with recent advances in measuring direct region-to-region functional connectivity, we mapped the classic V1 to V4 hierarchy in the human brain. Using empirical neural network (ENN) models parameterized by these empirical connections, we determined that hierarchical pathways (V1{leftrightarrow}V2{leftrightarrow}V3{leftrightarrow}V4) reduce representational dimensionality relative to more rapid, high-dimensional contributions from direct pathways (e.g., V1{leftrightarrow}V4). These results reveal complementary hierarchical and direct contributions and establish ENN modeling as a general approach for determining pathway-specific functions throughout the brain.

neuroscience↗

Regularized partial correlation provides reliable functional connectivity estimates while correcting for widespread confounding

Functional connectivity (FC) has been invaluable for understanding the brains communication network, with strong potential for enhanced FC approaches to yield additional insights. Unlike with the fMRI field-standard method of pairwise correlation, theory suggests that partial correlation can estimate FC without confounded and indirect connections. However, partial correlation FC can also display low repeat reliability, impairing the accuracy of individual estimates. We hypothesized that reliability would be increased by adding regularization, which can reduce overfitting to noise in regression-based approaches like partial correlation. We therefore tested several regularized alternatives - graphical lasso, graphical ridge, and principal component regression - against unregularized partial and pairwise correlation, applying them to empirical resting-state fMRI and simulated data. As hypothesized, regularization vastly improved reliability, quantified using between-session similarity and intraclass correlation. This enhanced reliability then granted substantially more accurate individual FC estimates when validated against structural connectivity (empirical data) and ground truth networks (simulations). Graphical lasso showed especially high accuracy among regularized approaches, seemingly by maintaining more valid underlying network structures. We additionally found graphical lasso to be robust to noise levels, data quantity, and subject motion - common fMRI error sources. Lastly, we demonstrated that resting-state graphical lasso FC can effectively predict fMRI task activations and individual differences in behavior, further establishing its reliability, external validity, and ability to characterize task-related functionality. We recommend graphical lasso or similar regularized methods for calculating FC, as they can yield more valid estimates of unconfounded connectivity than field-standard pairwise correlation, while overcoming the poor reliability of unregularized partial correlation.

neuroscience↗

Combined loss of obscurin and obscurin-like 1 in murine hearts results in impaired diastolic dysfunction, altered metabolism and deregulated mitophagy.

Muscle proteins of the obscurin protein family play important roles in sarcomere organization, sarcoplasmic reticulum (SR) and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood. To investigate the functional roles of obscurin and its close homologue obscurin-like 1 (Obsl1) in the heart, we generated and analyzed knockout mice for obscurin, Obsl1, as well as obscurin/Obsl1 double-knockouts (dKO). We show that dKO mice are viable but show postnatal deficits in cardiac muscle SR and mitochondrial architecture and function at the microscopic, biochemical and cellular level. Altered SR structure resulted in perturbed calcium cycling, while mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3, a Micos complex protein. Hearts of dKO mice also show increased expression of Atg4d, a novel Obsl1 interacting protein, resulting in abnormal mitophagy and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure. Taken together, our data suggest that obscurin and Obsl1 play crucial roles in cardiac SR structure, calcium cycling, mitochondrial function, turnover and metabolism.

cell biology↗

Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated in the tumor, leading to homologous recombination deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived xenograft PH039, which lacks demonstrable repair gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by repeated 21-day niraparib treatments in vivo. PH039 acquired PARPi resistance by the third cycle of treatment and demonstrated unimpeded growth during subsequent exposure to either niraparib or rucaparib. Transcriptional profiling throughout the time course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of RAD51C methylation in patient tumor samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated that loss of RAD51C methylation prior to on-study biopsy was associated with limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide an important model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

cancer biology↗