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Chesebro, A. G.

Publications and source records attributed to Chesebro, A. G..

5 recordsLinked to original sources

A biophysical corticostriatal model predicts learning-dependent 7T fMRI dynamics and individual reward bias in humans

Circuit-level computational models can do more than explain existing data; they can generate novel hypotheses and capture individual differences in human populations. We demonstrate this using a biophysical corticostriatal model, transforming simulated neuronal activity from local field potential (LFP) into functional magnetic resonance imaging (fMRI) signals via the balloon model, and finally generating behavioral outcomes. We then validate the results against those obtained from human subjects. The model generates a counterintuitive yet testable prediction. Although prefrontal-striatal coherence demonstrates an increase at the neural LFP scale during learning, the same circuit-- passed through the hemodynamic transform---predicts a decrease in prefrontal-striatal BOLD correlation, driven by category-selective representations that emerge in cortex but not striatum. This prediction is confirmed in fMRI data optimized for single-subject-level detection sensitivity. The model further enables single-subject fitting of a behavioral outcome, classifying individuals into those differentially responding to positive versus negative reward bias. Established biomarkers, including activation measured by the amplitude of low-frequency fluctuations and dopaminergic effects on hemodynamic latency, are also conserved across LFP and fMRI scales. These findings reposition circuit models as generative tools for human neuroscience, capable of producing mechanistically grounded hypotheses and parsing individual variation in ways inaccessible to data-driven approaches alone.

neuroscience↗

Spatially convergent fMRI signatures of diabetes and male sex identify genetic vulnerabilities to accelerated brain aging

Age-related cognitive decline results from complex interactions between neuroendocrine and neurometabolic processes that undergo lifelong degredation, yet the mechanisms underlying these interactions remain poorly understood. This study examined the effects of diabetes and sex on functional brain networks across aging through analysis of two large cohorts (N=1,621 total) using both 3T and 7T functional MRI, complemented by spatial transcriptomic data from over 14,000 genes from six post-mortem brains. Four networks-- cingulo-opercular, default mode, salience, and lateral somatomotor--exhibited significant functional decline in both individuals with diabetes and independently in males. Gene expression analysis of vulnerable networks revealed significant overexpression of insulin-dependent glucose transporters, dopaminergic and GABAergic synaptic genes, and VEGFA-VEGFR2 pathway components. These findings suggest functionally-specific circuit vulnerability to metabolic and hormonal dysregulation, potentially offering targets for early intervention before irreversible neurodegeneration occurs.

neuroscience↗

Leveraging Julia's automated differentiation and symbolic computation to increase spectral DCM flexibility and speed

Using neuroimaging and electrophysiological data to infer neural parameter estimations from theoretical circuits requires solving the inverse problem. Here, we provide a new Julia language package designed to i) compose complex dynamical models in a simple and modular way with ModelingToolkit.jl, ii) implement parameter fitting based on spectral dynamic causal modeling (sDCM) using the Laplace approximation, analogous to MATLAB implementation in SPM12, and iii) leverage Julias unique strengths to increase accuracy and speed by employing Automatic Differentiation during the fitting procedure. To illustrate the utility of our flexible modular approach, we provide a method to improve correction for fMRI scanner field strengths (1.5T, 3T, 7T) when fitting models to real data.

neuroscience↗

Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age.

Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we established their neuronal basis using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, age = 26.9 {+/-} 11.2 years, N = 36). Then, using the multi-scale Larter-Breakspear neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels.

neuroscience↗

Ion Gradient-driven Bifurcations of a Multi-Scale Neuronal Model

Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in the Larter-Breakspear neural mass model. We show the existence and locations of Neimark-Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials, and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients will cause decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects congruent with those observed in human neuroimaging studies.

neuroscience↗