Magnetic resonance elastography captures a transient benefit of exercise intervention on forebrain stiffness in a rat model of fetal alcohol spectrum disorders.

BACKGROUND: Fetal alcohol spectrum disorders (FASD), a group of prevalent conditions resulting from prenatal alcohol exposure, affect the maturation of cerebral white matter as first identified with neuroimaging. However, traditional methods are unable to track subtle microstructural alterations to white matter. This preliminary study uses a highly sensitive and clinically translatable magnetic resonance elastography (MRE) protocol to assess brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. METHODS: Female rat pups were either alcohol-exposed (AE) via intragastric intubation of alcohol in milk substitute (5.25 g/kg/day) or sham-intubated (SI) on postnatal days (PD) four through nine to model alcohol exposure during the brain growth spurt. On PD 30, half of AE and SI rats were randomly assigned to either a wheel-running or standard cage for 12 days. Magnetic resonance elastography was used to measure whole brain and callosal mechanical properties at the end of the intervention (around PD 42) and at 1 month post-intervention, and findings were validated with histological quantification of oligoglia. RESULTS: Alcohol exposure reduced forebrain stiffness (p = 0.02) in standard-housed rats. The adolescent exercise intervention mitigated this effect, confirming that increased aerobic activity supports proper neurodevelopmental trajectories. Forebrain damping ratio was lowest in standard-housed AE rats (p < 0.01), but this effect was not mitigated by intervention exposure. At 1 month post-intervention, all rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Callosal stiffness and damping ratio increased with age. With cessation of exercise, there was a negative rebound effect on the quantity of callosal oligodendrocytes, irrespective of treatment group, which diverged from our MRE results. CONCLUSIONS: This is the first application of MRE to measure the brain's mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes in forebrain stiffness and damping ratio. Additionally, MRE identified an exercise-related increase to forebrain stiffness in AE rats.

Minimizing Measurement-Induced Errors in Viscoelastic MR Elastography.

The inverse problem that underlies Magnetic Resonance Elastography (MRE) is sensitive to the measurement data and the quality of the results of this tissue elasticity imaging process can be influenced both directly and indirectly by measurement noise. In this work, we apply a coupled adjoint field formulation of the viscoelastic constitutive parameter identification problem, where the indirect influence of noise through applied boundary conditions is avoided. A well-posed formulation of the coupled field problem is obtained through conditions applied to the adjoint field, relieving the computed displacement field from kinematic errors on the boundary. The theoretical framework for this formulation via a nearly incompressible, parallel subdomain-decomposition approach is presented, along with verification and a detailed exploration of the performance of the methods via a numerical simulation study. In addition, the advantages of this novel approach are demonstrated in-vivo in the human brain, showing the ability of the method to obtain viable tissue property maps in difficult configurations, enhancing the accuracy of the method.

Monitoring lasting changes to brain tissue integrity through mechanical properties following adolescent exercise intervention in a rat model of Fetal Alcohol Spectrum Disorders.

Background: Fetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditions resulting from prenatal alcohol exposure. Alcohol exposure during the third trimester of pregnancy overlapping with the brain growth spurt is detrimental to white matter growth and myelination, particularly in the corpus callosum, ultimately affecting tissue integrity in adolescence. Traditional neuroimaging techniques have been essential for assessing neurodevelopment in affected youth; however, these methods are limited in their capacity to track subtle microstructural alterations to white matter, thus restricting their effectiveness in monitoring therapeutic intervention. In this preliminary study we use a highly sensitive and clinically translatable Magnetic Resonance Elastography (MRE) protocol for assessing brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. Methods: Rat pups were divided into two groups: alcohol-exposed (AE) pups which received alcohol in milk substitute (5.25 g/kg/day) via intragastric intubation on postnatal days (PD) four through nine during the rat brain growth spurt (Dobbing and Sands, 1979), or sham-intubated (SI) controls. In adolescence, on PD 30, half AE and SI rats were randomly assigned to either a modified home cage with free access to a running wheel or to a new home cage for 12 days (Gursky and Klintsova, 2017). Previous studies conducted in the lab have shown that 12 days of voluntary exercise intervention in adolescence immediately ameliorated callosal myelination in AE rats (Milbocker et al., 2022, 2023). MRE was used to measure longitudinal changes to mechanical properties of the whole brain and the corpus callosum at intervention termination and one-month post-intervention. Histological quantification of precursor and myelinating oligoglia in corpus callosum was performed one-month post-intervention. Results: Prior to intervention, AE rats had lower forebrain stiffness in adolescence compared to SI controls ( p = 0.02). Exercise intervention immediately mitigated this effect in AE rats, resulting in higher forebrain stiffness post-intervention in adolescence. Similarly, we discovered that forebrain damping ratio was lowest in AE rats in adolescence ( p < 0.01), irrespective of intervention exposure. One-month post-intervention in adulthood, AE and SI rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Taken together, these MRE data suggest that adolescent exercise intervention supports neurodevelopmental "catch-up" in AE rats. Analysis of the stiffness and damping ratio of the body of corpus callosum revealed that these measures increased with age. Finally, histological quantification of myelinating oligodendrocytes one-month post-intervention revealed a negative rebound effect of exercise cessation on the total estimate of these cells in the body of corpus callosum, irrespective of treatment group which was not convergent with noninvasive MRE measures. Conclusions: This is the first application of MRE to measure changes in brain mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes to forebrain stiffness and damping ratio in adolescence. These preliminary findings expand upon results from previous studies which used traditional diffusion neuroimaging to identify structural changes to the adolescent brain in rodent models of FASD (Milbocker et al., 2022; Newville et al., 2017). Additionally, in vivo MRE identified an exercise-related alteration to forebrain stiffness that occurred in adolescence, immediately post-intervention.

General guidelines for the performance of viscoelastic property identification in elastography: A Monte-Carlo analysis from a closed-form solution.

Identification of the mechanical properties of a viscoelastic material depends on characteristics of the observed motion field within the object in question. For certain physical and experimental configurations and certain resolutions and variance within the measurement data, the viscoelastic properties of an object may become non-identifiable. Elastographic imaging methods seek to provide maps of these viscoelastic properties based on displacement data measured by traditional imaging techniques, such as magnetic resonance and ultrasound. Here, 1D analytic solutions of the viscoelastic wave equation are used to generate displacement fields over wave conditions representative of diverse time-harmonic elastography applications. These solutions are tested through the minimization of a least squares objective function suitable for framing the elastography inverse calculation. Analysis shows that the damping ratio and the ratio of the viscoelastic wavelength to the size of the domain play critical roles in the form of this least squares objective function. In addition, it can be shown analytically that this objective function will contain local minima, which hinder discovery of the global minima via gradient descent methods.