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Adverse childhood experiences increase vulnerability to stress-provoked mental illnesses, such as anxiety/depression and substance use disorders, later in life. How these experiences shape the brain to lead to such disorders remains a mystery. Brain-wide imaging of neural activity in the adult raised with or without early life adversity (ELA) holds promise of finding clues. Longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) provides a methodology to follow brain-wide neural activity dynamics over time in awake-behaving animals. Mn(II) delivered systemically is taken up through voltage-gated calcium channels throughout the brain over 24-26h. Behavior is recorded in our custom arena during Mn(II) uptake. We capture an image of basal behavior (normal exploration) at 22h, and then expose mice to acute threat, predator odor (TMT, 2,3,5-Trimethyl-3-thiazoine), and image again at 26h (Uselman et al, 2020). Here we combine this MEMRI paired with behavior protocol to investigate the effects of ELA on responses to acute threat in normally reared (n=12) and maternally deprived mice (n=12) (ELA-/+). Dams with newborn pups were deprived of adequate bedding from day P2-P9, which induces elevated cortisol in the pups (Rice et al., 2008). At 10 weeks of age, mice +/- ELA were subject our paired behavior-MEMRI longitudinal procedure for both acute and delayed responses. After imaging, mice are sacrificed, brains perfusion fixed and serial sections stained by immunohistochemistry. MEMRI images were skull-stripped, spatially co-registered, and intensity normalized. To measure the degree of activity and relationships between brain regions we performed statistical parametric mapping (SPM), segmentation of 90 brain regions, cross-correlation analysis, and Louvain community detection. Predator stress increased defensive/avoidance behavior for both groups (p

Life-threatening events cause extreme fear, which evolves in vulnerable people into a debilitating mental illness--post-traumatic stress disorder (PTSD), affecting 6.8% of all Americans. Those who progress to PTSD display both anxiety-related (hyper-arousal) and depressive (avoidance) symptoms. PTSD is accompanied by changes in brain functional anatomy. Some experience relief from selective serotonin reuptake inhibitors (SSRI), some from a1 adrenergic receptor inhibitors, and some respond to combined inhibition of both noradrenergic and serotonergic transporters (NET and SERT), SNRI. Cross-talk between serotonergic and noradrenergic systems (SS and NS) is well known. Both are disturbed in PTSD. Early life adversity is a known risk factor for PTSD. There are no predictive or diagnostic tests, and no reliably effective prevention or intervention for PTSD. Using manganese-enhanced MRI (MEMRI) tract-tracing, we reported that SERT-KO mice have abnormal circuitry in the prelimbic system. To determine whether early life adversity affects this circuit and the behavioral and neural response by fear, SERT-KO and WT mice raised either normally or with maternal deprivation, were exposed to predator stress (PS) in young adulthood, a known naturalistic provocateur of persistent fear in rodents. We use the light-dark box to quantify behavior and Mn²⁺-enhanced MRI (MEMRI) to witness behavior and brain activity. Mn²⁺ increases the relaxation rate of protons in water in T₁-weighted pulse sequences, and thus produces a hyper-intense signal in T₁-weighted MRI. Mn²⁺ is a metabolic contrast agent that reports on neural activity by entering active neurons through voltage-gated Ca²⁺ channels, and is transported along axons tracing multi-synaptic circuitry when injected locally.

To determine optimal parameters for acquisition and processing of dynamic contrast-enhanced MRI (DCE-MRI) to detect small changes in near normal low blood-brain barrier (BBB) permeability.Using a contrast-to-noise ratio metric (K-CNR) for Ktrans precision and accuracy, the effects of kinetic model selection, scan duration, temporal resolution, signal drift, and length of baseline on the estimation of low permeability values was evaluated with simulations.The Patlak model was shown to give the highest K-CNR at low Ktrans . The Ktrans transition point, above which other models yielded superior results, was highly dependent on scan duration and tissue extravascular extracellular volume fraction (ve ). The highest K-CNR for low Ktrans was obtained when Patlak model analysis was combined with long scan times (10-30 min), modest temporal resolution (60 s/image), and long baseline scans (1-4 min). Signal drift as low as 3% was shown to affect the accuracy of Ktrans estimation with Patlak analysis.DCE acquisition and modeling parameters are interdependent and should be optimized together for the tissue being imaged. Appropriately optimized protocols can detect even the subtlest changes in BBB integrity and may be used to probe the earliest changes in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis.

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r_2/r_1 ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue.

Purpose: Hybrid positron emission tomography (PET)/magnetic resonance (MR) imaging systems have recently been built that allow functional and anatomical information obtained from PET and MR to be acquired simultaneously. The authors have developed a robust coregistration scheme for a first generation small animal PET/MR imaging system and illustrated the potential of this system to study intratumoral heterogeneity in a mouse model. Methods: An alignment strategy to fuse simultaneously acquired PET and MR data, using the MR imaging gradient coordinate system as the reference basis, was developed. The fidelity of the alignment was evaluated over multiple study sessions. In order to explore its robustness in vivo, the alignment strategy was applied to explore the heterogeneity of glucose metabolism in a xenograft tumor model, using ^(18)F-FDG-PET to guide the acquisition of localized ^1H MR spectra within a single imaging session. Results: The alignment method consistently fused the PET/MR data sets with subvoxel accuracy (registration error mean=0.55 voxels

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are widely used in vivo imaging technologies with both clinical and biomedical research applications. The strengths of MRI include high-resolution, high-contrast morphologic imaging of soft tissues; the ability to image physiologic parameters such as diffusion and changes in oxygenation level resulting from neuronal stimulation; and the measurement of metabolites using chemical shift imaging. PET images the distribution of biologically targeted radiotracers with high sensitivity, but images generally lack anatomic context and are of lower spatial resolution. Integration of these technologies permits the acquisition of temporally correlated data showing the distribution of PET radiotracers and MRI contrast agents or MR-detectable metabolites, with registration to the underlying anatomy. An MRI-compatible PET scanner has been built for biomedical research applications that allows data from both modalities to be acquired simultaneously. Experiments demonstrate no effect of the MRI system on the spatial resolution of the PET system and

The amphibian embryo undergoes radical tissue transformations during blastula and gastrula stages, but live observation of internal morphogenetic events by optical microscopy is not feasible due to the opacity of the early embryo. Here, we report on the use of microscopic magnetic resonance imaging (MRI) to directly follow morphogenetic movements during blastula and gastrula stages of the Xenopus laevis embryo. We compare three different MRI modalities that take advantage of the intrinsic contrast present in embryonic tissues: three-dimensional (3D) fat-imaging, 3D water-imaging, and 2D high-speed high-resolution imaging of early embryonic stages. We show that the features revealed by the intrinsic contrast correlate with the histological structure of the embryo. Using this tissue specific intrinsic contrast, the main embryonic tissues and internal tissue movements as well as archenteron invagination can be differentiated without cell labeling. We present 2D and 3D time-lapse sequences of early Xenopus embryonic development, spanning the stages from early blastula to the end of gastrula, which show the complex internal rearrangements of gastrulation in essentially real-time.

Resolution degradation due to gradient coil deformation and vibration in NMR microscopy is investigated using finite element analysis. From the analysis, deformations due to the Lorentz force can be as large as 1-10 μm depending on the gradient strength and coil frame material. Thus, these deformations can be one of the major resolution limiting factors in NMR microscopy. Coil vibration, which depends on the input current waveform and resolution degradation due to time-variant deformation and time-invariant deformation are investigated by numerical simulations.