Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring.

Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60). R-fMRI sessions were conducted under light anesthesia at both ages. Offspring reared with insufficient bedding (that is, maltreated) displayed enduring negative affective behaviors. Amygdala-prefrontal cortex (PFC) functional connectivity increased significantly from adolescence to adulthood in controls, but not in maltreated animals. We computed the fractional amplitude of low-frequency fluctuations (fALFF), an index of intrinsic brain activity, and found that fALFF in medial prefrontal cortex and anterior cingulate cortex (MPFC/ACC) increased significantly with age in controls but remained unchanged in maltreated animals during adolescence and adulthood. We used a seed-based analysis to explore changes in functional connectivity between this region and the whole brain. Compared with controls, maltreated animals demonstrated reduced functional connectivity between MPFC/ACC and left caudate/putamen across both ages. Functional connectivity between MPFC/ACC and right caudate/putamen showed a group by age interaction: decreased in controls but increased in maltreated animals. These data suggest that maltreatment induces vulnerability to psychopathology and is associated with differential developmental trajectories of prefrontal and subcortical circuits underlying affect regulation.

Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions.

The brain contains high concentrations of the amino acid N-acetyl-l-aspartate (NAA) and its' glutamate adduct N-acetyl-l-aspartylglutamate (NAAG), both synthesized primarily by and stored in neurons. Upon depolarization both are exported to extracellular fluid (ECF) with NAA targeted to oligodendrocytes and NAAG targeted to astrocytes where they are hydrolyzed by specific enzymes. While the functions of these substances are incompletely known, their unique tri-cellular metabolism is apparently vital to normal brain function. Canavan disease (CD) is a globally occurring but rare early-onset human spongiform leukodystrophy associated with inborn genetic errors affecting the activity of aspartoacylase (ASPA), the enzyme highly expressed in oligodendrocytes that hydrolyzes NAA. Several hypotheses attempt to explain how the lack of ASPA activity results in the inability of oligodendrocytes to build or maintain axon-enveloping myelin sheaths, a failure reflected in the CD syndrome by profound neurological disturbances. Based on evidence provided by recent studies, as well as on descriptions of several atypical mild cases of CD and of a singular human case of an inborn error where NAA cannot be synthesized, we provide insights into the possible genesis of the CD syndrome and many of its phenotypic expressions. In this article we also evaluate current hypotheses, and discuss possible clinical interventions that may be of value in treatment of CD.

State-dependent functional connectivity of rat olfactory system assessed by fMRI.

Functional connectivity between the piriform cortex and limbic and neocortical areas was assessed using functional magnetic resonance imaging (fMRI) of urethane anesthetized rats that spontaneously cycled between slow-wave and fast-wave states. Slow-wave and fast-wave states were determined indirectly through monitoring of respiration rate, which was confirmed to co-vary with state as determined by electrophysiological recordings. Previous electrophysiological data have suggested that the piriform cortex shifts between responsiveness to afferent odor input during fast-wave states and enhanced functional connectivity with limbic areas during slow-wave state. The present results demonstrate that fMRI-based resting state functional connectivity between the piriform cortex and both limbic and neocortical areas is enhanced during slow-wave state compared to fast-wave state using respiration as an indirect measure of state in urethane anesthetized rats. This state-dependent shift in functional connectivity may be important for sleep-dependent odor memory consolidation.

MOSES: multiple oversampled slabs EPI sequence.

A new technique is proposed which combines the advantages of phase encoded and multi-slice echo planar imaging (EPI) methods. Its principle is to interleave multiple phase encoded EPI slabs. This approach can provide a larger spatial coverage than multi-slice EPI for the same signal to noise ratio and total imaging time and a shorter minimum imaging time than 3D EPI for the same coverage and repetition time. Other advantages include availability of the steady state image contrasts and potentially lower acoustic noise and RF specific absorption rate compared to the standard multi-slice EPI. A full discussion of its potential as well as in vivo results at 1.5 and 3 Tesla are presented in this paper.

Magnetic resonance imaging: applications of novel methods in studies of porous media.

NMR imaging is finding broad applications in nonbiological areas including the study of fluid flow and fluid ingress in porous media. The porous media include at the one end mineral rocks and various building materials through various solid plastic materials to foodstuffs at the other end of the spectrum. The fluids within these various media range from crude oil and water mixtures, and water itself, to a range of organic solvents in plastic materials. This paper is concerned with the flow and ingress of water through Bentheimer sandstone and Ninian reservoir specimens, and also in solid nylon blocks.

Real-time flow measurements using echo-planar imaging.

The ultra-high-speed echo-planar imaging (EPI) method is combined with velocity encoding prior to EPI read-out, thereby allowing real-time measurement of flow. Results of EPI flow measurement experiments are presented on phantoms and human volunteers.

Observation of cerebrospinal fluid flow with echo-planar magnetic resonance imaging.

Using echo-planar (EP) magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) flow patterns have been demonstrated in the normal subject and patients with pathological conditions including communicating hydrocephalus, aqueduct stenosis and syringohydromyelia. Snap-shot imaging times of 128 ms allow detailed demonstration of transient intraventricular CSF flow patterns, which is not possible with conventional MRI. The potential of EPI as a method for qualitative and quantitative assessment of CSF dynamics is illustrated.

PEEP--a rapid chemical-shift imaging method.

The phase-encoded echo-planar (PEEP) technique, a variant of echo-planar imaging, is used to achieve simultaneous high-speed spatial and chemical-shift data acquisition. This technique is the 2DFT equivalent of the projection reconstruction echo-planar method for chemical-shift imaging. Examples of images and spectra obtained using the PEEP method are presented.

Measurement of T1 by echo-planar imaging and the construction of computer-generated images.

The high-speed echo-planar imaging (EPI) technique is used to obtain rapid T1 and spin density measurements by a two-point method. It is shown that neglect of edge effects in the slice selection procedure leads to significant systematic errors in T1. T1 maps for two young patients, obtained at 4.0 MHz, are presented. The T1 and spin density values obtained are used to produce computer-generated images in inversion recovery simulations. These results demonstrate marked improvement in image contrast without paying the time penalty incurred in real experiments, thereby greatly increasing patient throughput potential.

Chemical-shift imaging.

The echo-planar shift mapping (EPSM) technique, a variant of echo-planar imaging (EPI), is evaluated with theoretical studies using computer simulations and with experimental studies using fluorine resonances in phantoms. In situations where the signal-to-noise ratio permits, it is shown that EPSM can produce in a few seconds chemical-shift spectra at all points in a specified spin-density image corresponding to a selected slice. Applications of this technique are likely to be for proton and fluorine chemical-shift measurements and rapid studies of magnetic field inhomogeneities produced by magnet non-alignment and field shifts around magnetic materials.