Imaging of brain electric field networks.

We present a method for direct imaging of the electric field networks in the human brain from electroencephalography (EEG) data with much higher temporal and spatial resolution than functional MRI (fMRI), without the concomitant distortions. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, and in a direct comparison with standard EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain's 'reward circuit'. The technique uses the output from standard EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity, but also provides an inexpensive and portable alternative to function MRI (fMRI).

The Nature of the Action Potential.

We demonstrate that our recently developed theory of electric field wave propagation in anisotropic and inhomogeneous brain tissues, which has been shown to explain a broad range of observed coherent synchronous brain electrical processes, also explains the spiking behavior of single neurons, thus bridging the gap between the fundamental element of brain electrical activity (the neuron) and large-scale coherent synchronous electrical activity. Our analysis indicates that the membrane interface of the axonal cellular system can be mathematically described by a nonlinear system with several small parameters. This allows for the rigorous derivation of an accurate yet simpler nonlinear model following the formal small parameter expansion. The resulting action potential model exhibits a smooth, continuous transition from the linear wave oscillatory regime to the nonlinear spiking regime, as well as a critical transition to a non-oscillatory regime. These transitions occur with changes in the criticality parameter and include several different bifurcation types, representative of the various experimentally detected neuron types. This new theory overcomes the limitations of the Hodgkin-Huxley model, such as the inability to explain extracellular spiking, efficient brain synchronization, saltatory conduction along myelinated axons, and a variety of other observed coherent macroscopic brain electrical phenomena. We also show that the standard cable axon theory can be recovered by our approach, using the very crude assumptions of piece-wise homogeneity and isotropy. However, the diffusion process described by the cable equation is not capable of supporting action potential propagation across a wide range of experimentally reported axon parameters.

Neuronal avalanches: Sandpiles of self-organized criticality or critical dynamics of brain waves?

Analytical expressions for scaling of brain wave spectra derived from the general nonlinear wave Hamiltonian form show excellent agreement with experimental "neuronal avalanche" data. The theory of the weakly evanescent nonlinear brain wave dynamics [Phys. Rev. Research 2, 023061 (2020); J. Cognitive Neurosci. 32, 2178 (2020)] reveals the underlying collective processes hidden behind the phenomenological statistical description of the neuronal avalanches and connects together the whole range of brain activity states, from oscillatory wave-like modes, to neuronal avalanches, to incoherent spiking, showing that the neuronal avalanches are just the manifestation of the different nonlinear side of wave processes abundant in cortical tissue. In a more broad way these results show that a system of wave modes interacting through all possible combinations of the third order nonlinear terms described by a general wave Hamiltonian necessarily produces anharmonic wave modes with temporal and spatial scaling properties that follow scale free power laws. To the best of our knowledge this has never been reported in the physical literature and may be applicable to many physical systems that involve wave processes and not just to neuronal avalanches.

Critical brain wave dynamics of neuronal avalanches.

Analytical expressions for scaling of brain wave spectra derived from the general non-linear wave Hamiltonian form show excellent agreement with experimental "neuronal avalanche" data. The theory of the weakly evanescent non-linear brain wave dynamics reveals the underlying collective processes hidden behind the phenomenological statistical description of the neuronal avalanches and connects together the whole range of brain activity states, from oscillatory wave-like modes, to neuronal avalanches, to incoherent spiking, showing that the neuronal avalanches are just the manifestation of the different non-linear side of wave processes abundant in cortical tissue. In a more broad way these results show that a system of wave modes interacting through all possible combinations of the third order non-linear terms described by a general wave Hamiltonian necessarily produces anharmonic wave modes with temporal and spatial scaling properties that follow scale free power laws. To the best of our knowledge this has never been reported in the physical literature and may be applicable to many physical systems that involve wave processes and not just to neuronal avalanches.

An enigmatic pelagic fish with internalized red muscle: A future regional endotherm or forever an ectotherm?

Ectothermy and endothermy in extant fishes are defined by distinct integrated suites of characters. Although only ⁓0.1% of fishes are known to have endothermic capacity, recent discoveries suggest that there may still be uncommon pelagic fish species with yet to be discovered endothermic traits. Among the most rarely encountered marine fishes, the louvar Luvarus imperialis is a remarkable example of adaptive evolution as the only extant pelagic species in the order Acanthuriformes (including surgeonfishes, tangs, unicornfishes and Moorish idol). Magnetic resonance imaging and gross necropsy did not yield evidence of cranial or visceral endothermy but revealed a central-posterior distribution of myotomal red muscle that is a mixture of the character states typifying ectotherms (lateral-posterior) and red muscle endotherms (central-anterior). Dissection of a specimen confirmed, and an osteological proxy supported, that L. imperialis has not evolved the vascular rete that is vital to retaining heat in the red muscle. The combination of presumably relying on caudal propulsion while exhibiting internal red muscle without associated retia is unique to L. imperialis among all extant fishes, raising the macroevolutionary question of whether this species - in geologic timescales - will remain an ectotherm or evolve red muscle endothermy.

Critically synchronized brain waves form an effective, robust and flexible basis for human memory and learning.

The effectiveness, robustness, and flexibility of memory and learning constitute the very essence of human natural intelligence, cognition, and consciousness. However, currently accepted views on these subjects have, to date, been put forth without any basis on a true physical theory of how the brain communicates internally via its electrical signals. This lack of a solid theoretical framework has implications not only for our understanding of how the brain works, but also for wide range of computational models developed from the standard orthodox view of brain neuronal organization and brain network derived functioning based on the Hodgkin-Huxley ad-hoc circuit analogies that have produced a multitude of Artificial, Recurrent, Convolution, Spiking, etc., Neural Networks (ARCSe NNs) that have in turn led to the standard algorithms that form the basis of artificial intelligence (AI) and machine learning (ML) methods. Our hypothesis, based upon our recently developed physical model of weakly evanescent brain wave propagation (WETCOW) is that, contrary to the current orthodox model that brain neurons just integrate and fire under accompaniment of slow leaking, they can instead perform much more sophisticated tasks of efficient coherent synchronization/desynchronization guided by the collective influence of propagating nonlinear near critical brain waves, the waves that currently assumed to be nothing but inconsequential subthreshold noise. In this paper we highlight the learning and memory capabilities of our WETCOW framework and then apply it to the specific application of AI/ML and Neural Networks. We demonstrate that the learning inspired by these critically synchronized brain waves is shallow, yet its timing and accuracy outperforms deep ARCSe counterparts on standard test datasets. These results have implications for both our understanding of brain function and for the wide range of AI/ML applications.

IVIM Imaging of Paraspinal Muscles Following Moderate and High-Intensity Exercise in Healthy Individuals.

Background: Quantification of the magnitude and spatial distribution of muscle blood flow changes following exercise may improve our understanding of the effectiveness of various exercise prescriptions. Intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) is a technique that quantifies molecular diffusion and microvascular blood flow, and has recently gained momentum as a method to evaluate a muscle's response to exercise. It has also been shown to predict responses to exercise-based physical therapy in individuals with low back pain. However, no study has evaluated the sensitivity of IVIM-MRI to exercise of varying intensity in humans. Here, we aimed to evaluate IVIM signal changes of the paraspinal muscles in response to moderate and high intensity lumbar extension exercise in healthy individuals. Methods: IVIM data were collected in 11 healthy volunteers before and immediately after a 3-min bout of moderate and high-intensity resisted lumbar extension. IVIM data were analyzed to determine the average perfusion fraction (f), pseudo-diffusion coefficient (D*), and diffusion coefficient (D) in the bilateral paraspinal muscles. Changes in IVIM parameters were compared between the moderate and high intensity exercise bouts. Results: Exercise increased all IVIM parameters, regardless of intensity (p < 0.003). Moderate intensity exercise resulted in a 11.2, 19.6, and 3.5% increase in f, D* and D, respectively. High intensity exercise led to a similar increase in f (12.2%), but much greater changes in D* (48.6%) and D (7.9%). Conclusion: IVIM parameter increases suggest that both the moderate and high-intensity exercise conditions elicited measurable changes in blood flow (increased f and D*) and extravascular molecular diffusion rates (increased D), and that there was a dose-dependence of exercise intensity on D* and D.

Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.

PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD. THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP). RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings. CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.

Unveiling the third dimension in morphometry with automated quantitative volumetric computations.

As computed tomography and related technologies have become mainstream tools across a broad range of scientific applications, each new generation of instrumentation produces larger volumes of more-complex 3D data. Lagging behind are step-wise improvements in computational methods to rapidly analyze these new large, complex datasets. Here we describe novel computational methods to capture and quantify volumetric information, and to efficiently characterize and compare shape volumes. It is based on innovative theoretical and computational reformulation of volumetric computing. It consists of two theoretical constructs and their numerical implementation: the spherical wave decomposition (SWD), that provides fast, accurate automated characterization of shapes embedded within complex 3D datasets; and symplectomorphic registration with phase space regularization by entropy spectrum pathways (SYMREG), that is a non-linear volumetric registration method that allows homologous structures to be correctly warped to each other or a common template for comparison. Together, these constitute the Shape Analysis for Phenomics from Imaging Data (SAPID) method. We demonstrate its ability to automatically provide rapid quantitative segmentation and characterization of single unique datasets, and both inter-and intra-specific comparative analyses. We go beyond pairwise comparisons and analyze collections of samples from 3D data repositories, highlighting the magnified potential our method has when applied to data collections. We discuss the potential of SAPID in the broader context of generating normative morphologies required for meaningfully quantifying and comparing variations in complex 3D anatomical structures and systems.

Collective Synchronous Spiking in a Brain Network of Coupled Nonlinear Oscillators.

A network of propagating nonlinear oscillatory modes (waves) in the human brain is shown to generate collectively synchronized spiking activity (hypersynchronous spiking) when both amplitude and phase coupling between modes are taken into account. The nonlinear behavior of the modes participating in the network are the result of the nonresonant dynamics of weakly evanescent cortical waves that, as shown recently, adhere to an inverse frequency-wave number dispersion relation when propagating through an inhomogeneous anisotropic media characteristic of the brain cortex. This description provides a missing link between simplistic models of synchronization in networks of small amplitude phase coupled oscillators and in networks built with various empirically fitted models of pulse or amplitude coupled spiking neurons. Overall the phase-amplitude coupling mechanism presented in the Letter shows significantly more efficient synchronization compared to current standard approaches and demonstrates an emergence of collective synchronized spiking from subthreshold oscillations that neither phase nor amplitude coupling alone are capable of explaining.

Medical imaging of tissue engineering and regenerative medicine constructs.

Advancement of tissue engineering and regenerative medicine (TERM) strategies to replicate tissue structure and function has led to the need for noninvasive assessment of key outcome measures of a construct's state, biocompatibility, and function. Histology based approaches are traditionally used in pre-clinical animal experiments, but are not always feasible or practical if a TERM construct is going to be tested for human use. In order to transition these therapies from benchtop to bedside, rigorously validated imaging techniques must be utilized that are sensitive to key outcome measures that fulfill the FDA standards for TERM construct evaluation. This review discusses key outcome measures for TERM constructs and various clinical- and research-based imaging techniques that can be used to assess them. Potential applications and limitations of these techniques are discussed, as well as resources for the processing, analysis, and interpretation of biomedical images.

Varying diffusion time to discriminate between simulated skeletal muscle injury models using stimulated echo diffusion tensor imaging.

PURPOSE: Evaluate the relationship between muscle microstructure, diffusion time (Δ), and the diffusion tensor (DT) to identify the optimal Δ where changes in muscle fiber size may be detected. METHODS: The DT was simulated in models with histology informed geometry over a range of Δ with a stimulated echo DT imaging (DTI) sequence using the numerical simulation application DifSim. The difference in the DT at each Δ between healthy and injured skeletal muscle models was calculated, to identify the optimal Δ at which changes in muscle fiber size may be detected. The random permeable barrier model (RPBM) was used to estimate muscle microstructure from the simulated DT measurements, which were compared to the ground truth. RESULTS: Across all models, fractional anisotropy provided greater contrast between injured and control models than diffusivity measurements. Compared to control models, in atrophic injury models, the greatest difference in the DT was found between 90 ms and 250 ms. In models with acute edema, the contrast between injured and control muscle increased with increasing diffusion time, although these models had smaller mean fiber areas. RPBM systematically underestimated fiber size but accurately estimated surface area-to-volume ratio of simulated models. CONCLUSION: These findings may better inform pulse sequence parameter selection when performing DTI experiments in vivo. If only a single diffusion experiment can be performed, the selected Δ should be ~170 ms to maximize the ability to discriminate between different injury models. Ideally several diffusion times between 90 ms and 500 ms should be sampled in order to maximize diffusion contrast, particularly when the disease process is unknown.

Multiparametric MRI characterization of level dependent differences in lumbar muscle size, quality, and microstructure.

Magnetic resonance imaging (MRI) is a diagnostic tool that can be used to noninvasively assess lumbar muscle size and fatty infiltration, important biomarkers of muscle health. Diffusion tensor imaging (DTI) is an MRI technique that is sensitive to muscle microstructural features such as fiber size (an important biomarker of muscle health), which is typically only assessed using invasive biopsy techniques. The goal of this study was to establish normative values of level-dependent lumbar muscle size, fat signal fraction, and restricted diffusion assessed by MRI in a highly active population. Forty-two active-duty Marines were imaged using a (a) high-resolution anatomical, (b) fat-water separation, and (c) DT-MRI scan. The multifidus and erector spinae muscles were compared at each level using two-way repeated measures ANOVA. Secondary analysis included Three dimensional (3D) reconstructions to qualitatively assess lumbar muscle size, fatty infiltration, and fiber orientation via tractography. The erector spinae was found to be larger than the multifidus above L5, with lower fat signal fraction above L3, and a less restricted diffusion profile than the multifidus above L4, with this pattern reversed in the lower lumbar spine. 3D reconstructions demonstrated accumulations of epimuscular fat in the anterior and posterior regions of the lumbar musculature, with minimal intramuscular fatty infiltration. Tractography images demonstrated different orientations of adjacent lumbar musculature, which cannot be visualized with standard MRI pulse sequences. The level dependent differences found in this study provide a normative baseline, for which to better understand whole muscle and microstructural changes associated with aging, low back pain, and pathology.

Brain Waves: Emergence of Localized, Persistent, Weakly Evanescent Cortical Loops.

An inhomogeneous anisotropic physical model of the brain cortex is presented that predicts the emergence of nonevanescent (weakly damped) wave-like modes propagating in the thin cortex layers transverse to both the mean neural fiber direction and the cortex spatial gradient. Although the amplitude of these modes stays below the typically observed axon spiking potential, the lifetime of these modes may significantly exceed the spiking potential inverse decay constant. Full-brain numerical simulations based on parameters extracted from diffusion and structural MRI confirm the existence and extended duration of these wave modes. Contrary to the commonly agreed paradigm that the neural fibers determine the pathways for signal propagation in the brain, the signal propagation because of the cortex wave modes in the highly folded areas will exhibit no apparent correlation with the fiber directions. Nonlinear coupling of those linear weakly evanescent wave modes then provides a universal mechanism for the emergence of synchronized brain wave field activity. The resonant and nonresonant terms of nonlinear coupling between multiple modes produce both synchronous spiking-like high-frequency wave activity as well as low-frequency wave rhythms. Numerical simulation of forced multiple-mode dynamics shows that, as forcing increases, there is a transition from damped to oscillatory regime that can then transition quickly to a nonoscillatory state when a critical excitation threshold is reached. The resonant nonlinear coupling results in the emergence of low-frequency rhythms with frequencies that are several orders of magnitude below the linear frequencies of modes taking part in the coupling. The localization and persistence of these weakly evanescent cortical wave modes have significant implications in particular for neuroimaging methods that detect electromagnetic physiological activity, such as EEG and magnetoencephalography, and for the understanding of brain activity in general, including mechanisms of memory.

Regional variations in ex-vivo diffusion tensor anisotropy are associated with cardiomyocyte remodeling in rats after left ventricular pressure overload.

BACKGROUND: Pressure overload left ventricular (LV) hypertrophy is characterized by increased cardiomyocyte width and ventricle wall thickness, however the regional variation of this remodeling is unclear. Cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) may provide a non-invasive, comprehensive, and geometrically accurate method to detect regional differences in structural remodeling in hypertrophy. We hypothesized that DTI parameters, such as fractional and planar anisotropy, would reflect myocyte remodeling due to pressure overload in a regionally-dependent manner. METHODS: We investigated the regional distributions of myocyte remodeling in rats with or without transverse aortic constriction (TAC) via direct measurement of myocyte dimensions with confocal imaging of thick tissue sections, and correlated myocyte cross-sectional area and other geometric features with parameters of diffusivity from ex-vivo DTI in the same regions of the same hearts. RESULTS: We observed regional differences in several parameters from DTI between TAC hearts and SHAM controls. Consistent with previous studies, helix angles from DTI correlated strongly with those measured directly from histological sections (p < 0.001, R2 = 0.71). There was a transmural gradient in myocyte cross-sectional area in SHAM hearts that was diminished in the TAC group. We also found several regions of significantly altered DTI parameters in TAC LV compared to SHAM, especially in myocyte sheet angle dispersion and planar anisotropy. Among others, these parameters correlated significantly with directly measured myocyte aspect ratios. CONCLUSIONS: These results show that structural remodeling in pressure overload LV hypertrophy is regionally heterogeneous, especially transmurally, with a greater degree of remodeling in the sub-endocardium compared to the sub-epicardium. Additionally, several parameters derived from DTI correlated significantly with measurements of myocyte geometry from direct measurement in histological sections. We suggest that DTI may provide a non-invasive, comprehensive method to detect regional structural myocyte LV remodeling during disease.

JEDI: Joint Estimation Diffusion Imaging of macroscopic and microscopic tissue properties.

PURPOSE: A new method for enhancing the sensitivity of diffusion MRI (dMRI) by combining the data from single (sPFG) and double (dPFG) pulsed field gradient experiments is presented. METHODS: This method uses our JESTER framework to combine microscopic anisotropy information from dFPG experiments using a new method called diffusion tensor subspace imaging (DiTSI) to augment the macroscopic anisotropy information from sPFG data analyzed using our guided by entropy spectrum pathways method. This new method, called joint estimation diffusion imaging (JEDI), combines the sensitivity to macroscopic diffusion anisotropy of sPFG with the sensitivity to microscopic diffusion anisotropy of dPFG methods. RESULTS: Its ability to produce significantly more detailed anisotropy maps and more complete fiber tracts than existing methods within both brain white matter (WM) and gray matter (GM) is demonstrated on normal human subjects on data collected using a novel fast, robust, and clinically feasible sPFG/dPFG acquisition. CONCLUSIONS: The potential utility of this method is suggested by an initial demonstration of its ability to mitigate the problem of gyral bias. The capability of more completely characterizing the tissue structure and connectivity throughout the entire brain has broad implications for the utility and scope of dMRI in a wide range of research and clinical applications.

Universal theory of brain waves: from linear loops to nonlinear synchronized spiking and collective brain rhythms.

An inhomogeneous anisotropic physical model of the brain cortex is presented that predicts the emergence of non-evanescent (weakly damped) wave-like modes propagating in the thin cortex layers transverse to both the mean neural fiber direction and to the cortex spatial gradient. Although the amplitude of these modes stays below the typically observed axon spiking potential, the lifetime of these modes may significantly exceed the spiking potential inverse decay constant. Full brain numerical simulations based on parameters extracted from diffusion and structural MRI confirm the existence and extended duration of these wave modes. Contrary to the standard paradigm that the neural fibers determine the pathways for signal propagation in the brain, the signal propagation due to the cortex wave modes in highly folded areas will exhibit no apparent correlation with the fiber directions. The results are consistent with numerous recent experimental animal and human brain studies demonstrating the existence of electrostatic field activity in the form of traveling waves (including studies where neuronal connections were severed) and with wave loop induced peaks observed in EEG spectra. In addition, we demonstrate that the resonant and non-resonant terms of the nonlinear coupling between multiple modes produce both synchronous spiking-like high frequency wave activity as well as low frequency wave rhythms as a result of their unique dispersion properties. Numerical simulation of forced multiple mode dynamics shows that as forcing increases there is a transition from damped to oscillatory regime that subsequently decays away as over-excitation is reached. The resonant nonlinear coupling results in the emergence of low frequency rhythms with frequencies that are several orders of magnitude below the linear frequencies of modes taking part in the coupling. The localization and persistence of these cortical wave modes, and this new mechanism for understanding the nature of spiking behavior, have significant implications in particular for neuroimaging methods that detect electromagnetic physiological activity, such as EEG and MEG, and in general for the understanding of brain activity, including mechanisms of memory.

Symplectomorphic registration with phase space regularization by entropy spectrum pathways.

PURPOSE: The ability to register image data to a common coordinate system is a critical feature of virtually all imaging studies. However, in spite of the abundance of literature on the subject and the existence of several variants of registration algorithms, their practical utility remains problematic, as commonly acknowledged even by developers of these methods. METHODS: A new registration method is presented that utilizes a Hamiltonian formalism and constructs registration as a sequence of symplectomorphic maps in conjunction with a novel phase space regularization. For validation of the framework a panel of deformations expressed in analytical form is developed that includes deformations based on known physical processes in MRI and reproduces various distortions and artifacts typically present in images collected using these different MRI modalities. RESULTS: The method is demonstrated on the three different magnetic resonance imaging (MRI) modalities by mapping between high resolution anatomical (HRA) volumes, medium resolution diffusion weighted MRI (DW-MRI) and HRA volumes, and low resolution functional MRI (fMRI) and HRA volumes. CONCLUSIONS: The method has shown an excellent performance and the panel of deformations was instrumental to quantify its repeatability and reproducibility in comparison to several available alternative approaches.

Joint Estimation of Effective Brain Wave Activation Modes Using EEG/MEG Sensor Arrays and Multimodal MRI Volumes.

In this letter, we present a new method for integration of sensor-based multifrequency bands of electroencephalography and magnetoencephalography data sets into a voxel-based structural-temporal magnetic resonance imaging analysis by utilizing the general joint estimation using entropy regularization (JESTER) framework. This allows enhancement of the spatial-temporal localization of brain function and the ability to relate it to morphological features and structural connectivity. This method has broad implications for both basic neuroscience research and clinical neuroscience focused on identifying disease-relevant biomarkers by enhancing the spatial-temporal resolution of the estimates derived from current neuroimaging modalities, thereby providing a better picture of the normal human brain in basic neuroimaging experiments and variations associated with disease states.

Decreasing Compensatory Ability of Concentric Ventricular Hypertrophy in Aortic-Banded Rat Hearts.

The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems. To address this issue, the present study investigates the evolution of compensatory mechanisms, in response to overload, by integrating diffusion-tensor MRI, echocardiography, and intracellular and hemodynamic measurements within consistent computational simulations of aortic-banded rat hearts. This approach allows a comparison of the relative leverage of different cardiac properties (geometry, passive mechanical stiffness, fiber configuration, diastolic and peak calcium concentrations, calcium-binding affinity, and aortic impedance) to affect cardiac contraction. Measurements indicate that, following aortic banding, an ejection fraction (EF) of 75% was maintained, relative to control rats, despite significant remodeling of the left-ventricular wall thickness (increasing by ~90% over 4 weeks). Applying our framework, we identified the left-ventricular wall thickness (concentric hypertrophy) and the intracellular calcium dynamics as playing the dominant roles in preserving EF acutely, whereas the significance of hypertrophy decreased subsequently. This trend suggests an increasing reliance on intracellular mechanisms (average increase ~50%), rather than on anatomical features (average decrease ~60%), to achieve compensation of pump function in the early phase of heart failure.