Hanbing Lu

Synchronized delta oscillations correlate with the resting-state functional MRI signal

Synchronized low-frequency spontaneous fluctuations of the functional MRI (fMRI) signal have recently been applied to investigate large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations remain largely unknown. To this end, electrophysiological recordings and resting-state fMRI measurements were conducted in α-chloralose-anesthetized rats. Using a seed-voxel analysis strategy, region-specific, anesthetic dose-dependent fMRI resting-state functional connectivity was detected in bilateral primary somatosensory cortex (S1FL) of the resting brain. Cortical electroencephalographic signals were also recorded from bilateral S1FL; a visual cortex locus served as a control site. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in the γ bands, the resting-state fMRI signal correlates with the power coherence in low-frequency bands, particularly the δ band. These data indicate that hemodynamic fMRI signal differentially registers specific electrical oscillatory frequency band activity, suggesting that fMRI may be able to distinguish the ongoing from the evoked activity of the brain.

Rat brains also have a default mode network

The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychological disorders. However, its function(s) remains poorly understood. We show that rats possess a DMN that is broadly similar to the DMNs of nonhuman primates and humans. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent DMN appears to be a fundamental feature in the mammalian brain whose primary functions might be to integrate multimodal sensory and affective information to guide behavior in anticipation of changing environmental contingencies.

Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI)

Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity based on the passage of Mn2+ into active neurons. Because this mechanism is independent of any hemodynamic response, it is potentially ideal for pharmacological studies and was applied to investigate the acute CNS effects of cocaine in the rat. Dose-dependent, region-specific MEMRI signals were seen mostly in cortical and subcortical mesocorticolimbic structures. To verify the spatial accuracy and physiological mechanisms of MEMRI, neuronal activation following electrical forepaw stimulation revealed somatotopic signal enhancement in the primary and secondary somatosensory cortices, which was blocked by diltiazem, a Ca2+ channel antagonist. These data suggest that MEMRI may serve as a tool for investigating the effects of pharmacological agents and opens an application of MRI to study CNS drug effects at a systems level.

Large-scale brain networks in the awake, truly resting marmoset monkey.

Resting-state functional MRI is a powerful tool that is increasingly used as a noninvasive method for investigating whole-brain circuitry and holds great potential as a possible diagnostic for disease. Despite this potential, few resting-state studies have used animal models (of which nonhuman primates represent our best opportunity of understanding complex human neuropsychiatric disease), and no work has characterized networks in awake, truly resting animals. Here we present results from a small New World monkey that allows for the characterization of resting-state networks in the awake state. Six adult common marmosets (Callithrix jacchus) were acclimated to light, comfortable restraint using individualized helmets. Following behavioral training, resting BOLD data were acquired during eight consecutive 10 min scans for each conscious subject. Group independent component analysis revealed 12 brain networks that overlap substantially with known anatomically constrained circuits seen in the awake human. Specifically, we found eight sensory and “lower-order” networks (four visual, two somatomotor, one cerebellar, and one caudate–putamen network), and four “higher-order” association networks (one default mode-like network, one orbitofrontal, one frontopolar, and one network resembling the human salience network). In addition to their functional relevance, these network patterns bear great correspondence to those previously described in awake humans. This first-of-its-kind report in an awake New World nonhuman primate provides a platform for mechanistic neurobiological examination for existing disease models established in the marmoset.

Physiologically evoked neuronal current MRI in a bloodless turtle brain: detectable or not?

Contradictory reports regarding the detection of neuronal currents have left the feasibility of neuronal current MRI (ncMRI) an open question. Most previous ncMRI studies in human subjects are suspect due to their inability to separate or eliminate hemodynamic effects. In this study, we used a bloodless turtle brain preparation that eliminates hemodynamic effects, to explore the feasibility of detecting visually-evoked ncMRI signals at 9.4 T. Intact turtle brains, with eyes attached, were dissected from the cranium and placed in artificial cerebral spinal fluid. Light flashes were delivered to the eyes to evoke neuronal activity. Local field potential (LFP) and MRI signals were measured in an interleaved fashion. Robust visually-evoked LFP signals were observed in turtle brains, but no significant signal changes synchronized with neuronal currents were found in the ncMRI images. In this study, detection thresholds of 0.1% and 0.1 degrees were set for MRI magnitude and phase signal changes, respectively. The absence of significant signal changes in the MRI images suggests that visually-evoked ncMRI signals in the turtle brain are below these detectable levels.

Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T.

In cerebral blood volume (CBV)‐weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV‐weighted fMRI are based upon the susceptibility effect, to which spin‐echo and gradient‐echo sequences have different sensitivities. In the present study, CBV‐weighted fMRI was conducted using spin‐echo and gradient‐echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV‐weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76 ± 12% of the observed spin‐echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation‐induced CBV changes at high field. Magn Reson Med 58:616–621, 2007.

Post-treatment with amphetamine enhances reinnervation of the ipsilateral side cortex in stroke rats

Amphetamine (AM) treatment has been shown to alter behavioral recovery after ischemia caused by embolism, permanent unilateral occlusion of the common carotid and middle cerebral arteries, or unilateral sensorimotor cortex ablation in rats. However, the behavioral results are inconsistent possibly due to difficulty controlling the size of the lesion before treatment. There is also evidence that AM promotes neuroregeneration in the cortex contralateral to the infarction; however, the effects of AM in the ipsilateral cortex remain unclear. The purpose of this study was to employ T2-weighted imaging (T2WI) to establish controlled criteria for AM treatment and to examine neuroregenerative effects in both cortices after stroke. Adult rats were anesthetized, and the right middle cerebral artery was ligated for 90 min to generate lesions in the ipsilateral cortex. Animals were separated into two equal treatment groups (AM or saline) according to the size of infarction, measured by T2WI at 2days after stroke. AM or saline was administered to stroke rats every third day starting on day 3 for 4weeks. AM treatment significantly reduced neurological deficits, as measured by body asymmetry and Bedersons score. T2WI and diffusion tensor imaging (DTI) were used to examine the size of infarction and axonal reinnervation, respectively, before and following treatment on days 2, 10 and 25 after stroke. AM treatment reduced the volume of tissue loss on days 10 and 25. A significant increase in fractional anisotropy ratio was found in the ipsilateral cortex after repeated AM administration, suggesting a possible increase in axonal outgrowth in the lesioned side cortex. Western analysis indicated that AM significantly increased the expression of synaptophysin ipsilaterally and neurofilament bilaterally. AM also enhanced matrix metalloproteinase (MMP) enzymatic activity, determined by MMP zymography in the lesioned side cortex. qRT-PCR was used to examine the expression of trophic factors after the 1st and 2nd doses of AM or saline injection. The expression of BDNF, but not BMP7 or CART, was significantly enhanced by AM in the lesioned side cortex. In conclusion, post-stroke treatment with AM facilitates behavioral recovery, which is associated with an increase in fractional anisotropy activity, enhanced fiber growth in tractography, synaptogenesis, upregulation of BDNF, and MMP activity mainly in the lesioned cortex. Our data suggest that the ipsilateral cortex may be the major target of action in stroke brain after AM treatment.

Registering and Analyzing Rat fMRI Data in the Stereotaxic Framework by Exploiting Intrinsic Anatomical Features

The value of analyzing neuroimaging data on a group level has been well established in human studies. However, there is no standard procedure for registering and analyzing functional magnetic resonance imaging (fMRI) data into common space in rodent fMRI studies. An approach for performing rat imaging data analysis in the stereotaxic framework is presented. This method is rooted in the biological observation that the skull shape and size of rat brain are essentially the same as long as their weights are within certain range. Registration is performed using rigid-body transformations without scaling or shearing, preserving the unique properties of the stable shape and size inherent in rat brain structure. Also, it does not require brain tissue masking and is not biased towards surface coil sensitivity profile. A standard rat brain atlas is used to facilitate the identification of activated areas in common space, allowing accurate region of interest analysis. This technique is evaluated from a group of rats (n=11) undergoing routine MRI scans; the registration accuracy is estimated to be within 400 microm. The analysis of fMRI data acquired with an electrical forepaw stimulation model demonstrates the utility of this technique. The method is implemented within the Analysis of Functional NeuroImages (AFNI) framework and can be readily extended to other studies.

Constituents and functional implications of the rat default mode network.

Significance The default mode network (DMN) has been suggested to support a variety of internal-state functions in human. Because preclinical models can be used in translational studies of neuropsychiatric disorders, investigations of the DMN in these models may aid the understanding of both physiology and pathophysiology of the human DMN. To our knowledge, this is the first study to investigate the constituents and functional implications of the rat DMN. We provide empirical evidence that the rat DMN is composed of highly connected anatomical and functional subnetworks, which show differential modulation in association with age-related cognitive dysfunction. These findings provide a framework to further explore the physiological basis and behavioral significance of the rodent DMN. The default mode network (DMN) has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation within the network. Because preclinical models can inform translational studies of neuropsychiatric disorders, partitioning of the DMN in nonhuman species, which has previously not been reported, may inform both physiology and pathophysiology of the human DMN. In this study, we sought to identify constituents of the rat DMN using resting-state functional MRI (rs-fMRI) and diffusion tensor imaging. After identifying DMN using a group-level independent-component analysis on the rs-fMRI data, modularity analyses fractionated the DMN into an anterior and a posterior subsystem, which were further segregated into five modules. Diffusion tensor imaging tractography demonstrates a close relationship between fiber density and the functional connectivity between DMN regions, and provides anatomical evidence to support the detected DMN subsystems. Finally, distinct modulation was seen within and between these DMN subcomponents using a neurocognitive aging model. Taken together, these results suggest that, like the human DMN, the rat DMN can be partitioned into several subcomponents that may support distinct functions. These data encourage further investigation into the neurobiological mechanisms of DMN processing in preclinical models of both normal and disease states.

Low- but Not High-Frequency LFP Correlates with Spontaneous BOLD Fluctuations in Rat Whisker Barrel Cortex

Resting-state magnetic resonance imaging (rsMRI) is thought to reflect ongoing spontaneous brain activity. However, the precise neurophysiological basis of rsMRI signal remains elusive. Converging evidence supports the notion that local field potential (LFP) signal in the high-frequency range correlates with fMRI response evoked by a task (e.g., visual stimulation). It remains uncertain whether this relationship extends to rsMRI. In this study, we systematically modulated LFP signal in the whisker barrel cortex (WBC) by unilateral deflection of rat whiskers. Results show that functional connectivity between bilateral WBC was significantly modulated at the 2 Hz, but not at the 4 or 6 Hz, stimulus condition. Electrophysiologically, only in the low-frequency range (<5 Hz) was the LFP power synchrony in bilateral WBC significantly modulated at 2 Hz, but not at 4- or 6-Hz whisker stimulation, thus distinguishing these 2 experimental conditions, and paralleling the findings in rsMRI. LFP power synchrony in other frequency ranges was modulated in a way that was neither unique to the specific stimulus conditions nor parallel to the fMRI results. Our results support the hypothesis that emphasizes the role of low-frequency LFP signal underlying rsMRI.