min Li

Developmental Changes in Diffusion Anisotropy Coincide with Immature Oligodendrocyte Progression and Maturation of Compound Action Potential

Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte lineage progression and functional maturation of axons to structural development of selected cerebral white-matter tracts as determined by diffusion tensor imaging (DTI). Immunohistochemical studies showed that late oligodendrocyte progenitors appear at gestational age 22 [embryonic day 22 (E22)], whereas immature oligodendrocytes appear at E25, and both increase rapidly with time (∼13 cells/mm2/d) until the onset of myelination. Myelination began at postnatal day 5 (P5) (E36) in the internal capsule (IC) and at P11 in the medial corpus callosum (CC), as determined by localization of sodium channels and myelin basic protein. DTI of the CC and IC showed that fractional anisotropy (FA) increased rapidly between E25 and P1 (E32) (∼11% per day) and plateaued (<5% per day) after the onset of myelination. Postnatal maturation of the compound action potential (CAP) showed a developmental pattern similar to FA, with a rapid rise between E29 and P5 (in the CC, 18% per day) and a slower rise from P5 to P11 (in the CC, <5% per day). The development of immature oligodendrocytes after E29 coincides with changes in FA and CAP area in both the CC and IC. These findings suggest that developmental expansion of immature oligodendrocytes during the premyelination period may be important in defining structural and functional maturation of the white matter.

Impaired eyeblink conditioning and decreased hippocampal volume in PDAPP V717F mice

We examined heterozygous transgenic (Tg) mice that overexpress V717F amyloid precursor protein (APP) for delay eyeblink conditioning (EBC) and hippocampal volume with magnetic resonance imaging (MRI). Platelet-derived APP mice were significantly impaired on EBC relative to wild type (WT) litter-mate controls. T2-weighted spin echo images (62.5 x 125 x 500 microm) of the same mice were acquired under anesthesia using a 9.4T magnet. Tg mice had hippocampal to brain volume ratios that were significantly smaller than WT controls (31% smaller in the rostral dorsal hippocampus, 13-22% smaller among equal dorsal-ventral thirds of a caudal section). These results indicate that overexpression of APP or beta amyloid profoundly affects learning and memory and hippocampal volume. The results also indicate that eyeblink conditioning and quantitative MRI in mice may be useful assays to follow the progression of disease-related changes, and to test the effectiveness of potential therapeutics against Alzheimers disease.

fmri of visual system activation in the conscious rabbit

A conscious rabbit preparation developed for fMRI, and the results from visual stimulation studies at a 4.7T magnetic field are described. The rabbit is ideal for these experiments because of its natural tolerance for restraint. High spatial and temporal resolution magnetic resonance images, without movement artifacts, were obtained during long periods of restraint. Functional activation in primary visual cortex and lateral geniculate nucleus (LGN) were reproducibly observed in response to light stimulus. In comparison to existing anesthetized animal models, a functional response free of the anesthetic modulation can be recorded with the new approach. The conscious animal model can be applied to functional studies of sensory systems, learning and memory, and drug‐induced cerebral activation. Magn Reson Med 44:474–478, 2000.

Effects of anesthesia on BOLD signal and neuronal activity in the somatosensory cortex

Most functional magnetic resonance imaging (fMRI) animal studies rely on anesthesia, which can induce a variety of drug-dependent physiological changes, including depression of neuronal activity and cerebral metabolism as well as direct effects on the vasculature. The goal of this study was to characterize the effects of anesthesia on the BOLD signal and neuronal activity. Simultaneous fMRI and electrophysiology were used to measure changes in single units (SU), multi-unit activity (MUA), local field potentials (LFP), and the blood oxygenation level-dependent (BOLD) response in the somatosensory cortex during whisker stimulation of rabbits before, during and after anesthesia with fentanyl or isoflurane. Our results indicate that anesthesia modulates the BOLD signal as well as both baseline and stimulus-evoked neuronal activity, and, most significantly, that the relationship between the BOLD and electrophysiological signals depends on the type of anesthetic. Specifically, the behavior of LFP observed under isoflurane did not parallel the behavior of BOLD, SU, or MUA. These findings suggest that the relationship between these signals may not be straightforward. BOLD may scale more closely with the best measure of the excitatory subcomponents of the underlying neuronal activity, which may vary according to experimental conditions that alter the excitatory/inhibitory balance in the cortex.

A fiber optic-based system for behavioral eyeblink measurement in a MRI environment

We previously described a reliable system to control the timing of multiple stimuli and to detect behavioral eyeblink responses in fMRI studies of learning in animals. Here, we report a significant advancement of the original system, which incorporates a fiber-optic probe in order to avoid the interference associated with the application of pulsed field gradients during MR imaging, particularly echo planar imaging. Eyeblink responses recorded with our fiber-optic probe and modified detection circuit demonstrate the ability of our new system to acquire behavioral data free of gradient-induced artifacts, thereby eliminating the need for low-pass filtering. This fiber optic-based system should be applicable to both animal and human imaging experiments.

A MRI-compatible system for whisker stimulation.

We describe here a system for whisker stimulation designed for functional studies in high-field magnetic resonance imaging (MRI) environments. This system, which incorporates real-time optical monitoring of the vibration stimulus, can generate well-controlled and reproducible whisker deflections with amplitudes up to 2mm and frequencies up to 75 Hz, suitable for functional magnetic resonance imaging (fMRI) studies of animals. Whiskers on either or both sides of the head can be stimulated selectively during fMRI experiments without removing the subject from the magnet. With a user-friendly graphical interface of a computer, a user can conveniently control both the whisker vibration and gating of the MR imager, and synchronize the stimulation with the fMRI acquisition to ensure precise timing of the stimulus presentation. This whisker stimulation system should facilitate a wide variety of fMRI investigations of the neural systems mediating sensory information from the whiskers.

Functional magnetic resonance imaging in the awake rabbit: a system for stimulus presentation and response detection during eyeblink conditioning

We describe a reliable system to control the timing of multiple stimuli and to detect eyeblink responses during functional magnetic resonance imaging (fMRI). The methods for stimulus delivery and timing, eyeblink detection, and response quantification are described in detail. We are using these methods in awake rabbits to study eyeblink conditioning (EBC) as a model paradigm for the study of learning and memory. Examples of conditioned eyeblinks in the awake rabbit during fMRI are presented for validation of our techniques. The results indicate that eyeblinks can be reliably recorded during fMRI, and that neither the stimulus delivery nor the response detection interferes with each other or affect the quality of the images. The combined fMRI/behavioral techniques should be useful for examining the entire brain simultaneously during the associative learning of a conditioned reflex in an animal model system.

Design of an MR image processing module on an FPGA chip

We describe the design and implementation of an image processing module on a single-chip Field-Programmable Gate Array (FPGA) for real-time image processing. We also demonstrate that through graphical coding the design work can be greatly simplified. The processing module is based on a 2D FFT core. Our design is distinguished from previously reported designs in two respects. No off-chip hardware resources are required, which increases portability of the core. Direct matrix transposition usually required for execution of 2D FFT is completely avoided using our newly-designed address generation unit, which saves considerable on-chip block RAMs and clock cycles. The image processing module was tested by reconstructing multi-slice MR images from both phantom and animal data. The tests on static data show that the processing module is capable of reconstructing 128×128 images at speed of 400 frames/second. The tests on simulated real-time streaming data demonstrate that the module works properly under the timing conditions necessary for MRI experiments.

Mapping Rabbit Whisker Barrels Using Discriminant Analysis of High Field fMRI Data

High field (>4T) functional magnetic resonance imaging (fMRI) techniques provide increased spatial resolution that enables the noninvasive, repeatable study of the sensory cortices at the level of their basic functional units. The examination of these units is important for studies of sensory information processing, learning- or experience-related brain plasticity, or the fundamental relationship between hemodynamic and neuronal activity. However functional units cannot always be distinguished from their surrounding areas by conventional activation mapping methods such as correlation or hypothesis tests, which only consider temporal variation within each individual voxel. We report a novel method to detect individual whisker barrels by using discriminant analysis to jointly characterize high order dependency among multiple voxels. Our results in the whisker barrel cortex of the awake rabbit indicate that the proposed method can differentiate reliably small clusters of activated voxels corresponding to individual whisker barrels within larger areas of functional activation, even in the case of adjacent whiskers in unanesthetized subjects. This method is computationally efficient, requires no specific experimental design for fMRI acquisition, and should be applicable to studies of other sensory systems.

Blood oxygenation level dependent signal and neuronal adaptation to optogenetic and sensory stimulation in somatosensory cortex in awake animals.

The adaptation of neuronal responses to stimulation, in which a peak transient response is followed by a sustained plateau, has been well‐studied. The blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal has also been shown to exhibit adaptation on a longer time scale. However, some regions such as the visual and auditory cortices exhibit significant BOLD adaptation, whereas other such as the whisker barrel cortex may not adapt. In the sensory cortex a combination of thalamic inputs and intracortical activity drives hemodynamic changes, although the relative contributions of these components are not entirely understood. The aim of this study is to assess the role of thalamic inputs vs. intracortical processing in shaping BOLD adaptation during stimulation in the somatosensory cortex. Using simultaneous fMRI and electrophysiology in awake rabbits, we measured BOLD, local field potentials (LFPs), single‐ and multi‐unit activity in the cortex during whisker and optogenetic stimulation. This design allowed us to compare BOLD and haemodynamic responses during activation of the normal thalamocortical sensory pathway (i.e., both inputs and intracortical activity) vs. the direct optical activation of intracortical circuitry alone. Our findings show that whereas LFP and multi‐unit (MUA) responses adapted, neither optogenetic nor sensory stimulation produced significant BOLD adaptation. We observed for both paradigms a variety of excitatory and inhibitory single unit responses. We conclude that sensory feed‐forward thalamic inputs are not primarily responsible for shaping BOLD adaptation to stimuli; but the single‐unit results point to a role in this behaviour for specific excitatory and inhibitory neuronal sub‐populations, which may not correlate with aggregate neuronal activity.