Jun-Cheng Weng

Functional Mapping of Rat Barrel Activation Following Whisker Stimulation Using Activity-Induced Manganese-Dependent Contrast

BACKGROUND Cortical whisker barrels in the primary somatosensory cortex are a well-known example of brain function in rodents. The well-defined relationship between barrels and whiskers makes this system a unique model to study neuronal function and plasticity. In this study, we sought to establish a feasible working protocol of applying manganese-enhanced MRI (MEMRI) to map the cortical barrels following whisker stimulation. METHODS The protocol was based on the principle of activity-induced manganese-dependent (AIM) contrast. Rats were prepared by sodium pentobarbital anesthetization, intraperitoneal manganese-chloride injection, right common carotid mannitol injection and temperature maintenance. Left whiskers were connected to a speaker through a cotton thread and were stimulated by a series of rectangular pulses. MEMRI was acquired with a 3T scanner 3 h after whisker stimulation. Before MR scanning, Wistar rats were euthanized to avoid motion artifacts. To improve the signal-to-noise ratio (SNR) and detection sensitivity, image coregistration, pixel intensity normalization, statistical mapping, group averaging and subtraction were performed. The AIM enhancement of the cortical barrels was quantified using volume of interest analysis on the acquired T1WI and R1 mapping. RESULTS Both experimental and control groups showed greater enhancement in the right hemisphere, same side as mannitol injection. In the experimental group, however, activity-induced enhancement was more localized in the right barrel fields, whereas in the control group, the enhancement was uniform throughout the right cortex. In the right cortical barrels, the enhancement ratios and R1 values in the experimental group were significantly higher than those in the control group. In the left cortical barrels, there was no significant difference between the two groups. Subtracted images and voxel-based statistical t-value mapping between experimental and control groups showed additional enhancement concentrated in the right cortical barrels. CONCLUSIONS We have mapped rat whisker barrels using the AIM method and have shown a clear relationship between manganese-enhanced cortical regions and whisker tactile-sense-evoked activity. It is possible that, with sufficient SNR, the AIM method may reach whisker barrel discrimination, potentially useful to study plasticity in surgically or genetically manipulated rat brains.

Modularly Assembled Magnetite Nanoparticles Enhance in Vivo Targeting for Magnetic Resonance Cancer Imaging

Modularly assembled targeting nanoparticles were synthesized through self-assembly of targeting moieties on surfaces of functional nanoparticles. Specific molecular recognition of nickel nitrilotriacetate on Fe3O4 nanoparticles with hexahistidine tag on RGD4C peptides results in precisely controlled orientation of the targeting peptides. Better selectivity of the self-assembled RGD4C-Fe3O4 nanoparticles targeting oral cancer cells than that achievable through a conventional chemical cross-link strategy was demonstrated by means of atomic absorption spectrometry (AAS). An oral cancer hamster model was applied to reveal specific in vivo targeting and MR molecular imaging contrast in cancer lesions expressing alphavbeta3 integrin. Both AAS and MRI revealed that the self-assembled nanoparticles improved the targeting efficiency and reduced the hepatic uptake as compared with the conventional chemical cross-link particles. We investigated the biosafety, biodistribution, and kinetics of the nanoparticles and found that the nanoparticles were significantly cleared from the liver and kidneys after one week. By recombining the desired targeting moiety and various functional nanoparticles through self-assembly, this new modularly designed platform has the capability of enhancing the efficiency of targeted diagnosis and therapies for a wide spectrum of biomedical applications.

Assessment of abnormal brain structures and networks in major depressive disorder using morphometric and connectome analyses

BACKGROUND It is hypothesized that the phenomenology of major depressive disorder (MDD) is subserved by disturbances in the structure and function of brain circuits; however, findings of structural abnormalities using MRI have been inconsistent. Generalized q-sampling imaging (GQI) methodology provides an opportunity to assess the functional integrity of white matter tracts in implicated circuits. METHODS The study population was comprised of 16 outpatients with MDD (mean age 44.81±2.2 years) and 30 age- and gender-matched healthy controls (mean age 45.03±1.88 years). We excluded participants with any other primary mental disorder, substance use disorder, or any neurological illnesses. We used T1-weighted 3D MRI with voxel-based morphometry (VBM) and vertex-wise shape analysis, and GQI with voxel-based statistical analysis (VBA), graph theoretical analysis (GTA) and network-based statistical (NBS) analysis to evaluate brain structure and connectivity abnormalities in MDD compared to healthy controls correlates with clinical measures of depressive symptom severity, Hamilton Depression Rating Scale 17-item (HAMD) and Hospital Anxiety and Depression Scale (HADS). RESULTS Using VBM and vertex-wise shape analyses, we found significant volumetric decreases in the hippocampus and amygdala among subjects with MDD (p<0.001). Using GQI, we found decreases in diffusion anisotropy in the superior longitudinal fasciculus and increases in diffusion probability distribution in the frontal lobe among subjects with MDD (p<0.01). In GTA and NBS analyses, we found several disruptions in connectivity among subjects with MDD, particularly in the frontal lobes (p<0.05). In addition, structural alterations were correlated with depressive symptom severity (p<0.01). LIMITATIONS Small sample size; the cross-sectional design did not allow us to observe treatment effects in the MDD participants. CONCLUSIONS Our results provide further evidence indicating that MDD may be conceptualized as a brain disorder with abnormal circuit structure and connectivity.

Visualizing oxidative stress-induced depression of cardiac vagal baroreflex by MRI/DTI in a mouse neurogenic hypertension model

A clinical hallmark of hypertension is impairment of the cardiac vagal baroreflex, which maintains stable blood pressure and heart rate under physiological conditions. There is also evidence that oxidative stress in the brain is associated with neurogenic hypertension. We tested the hypothesis that an augmented superoxide level in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents, contributes to the depression of cardiac vagal baroreflex by disrupting the connectivity between the NTS and the nucleus ambiguus (NA), the origin of the vagus nerve, during neurogenic hypertension. An experimental model of neurogenic hypertension that employed intracerebroventricular infusion of angiotensin II in male adult C57BL/6 mice was used. Based on tractographic evaluations using magnetic resonance imaging/diffusion tensor imaging of the medulla oblongata in the brain stem, we found that the connectivity between the NTS and NA was disrupted in neurogenic hypertension, concurrent with impairment of the cardiac vagal baroreflex as detected by radiotelemetry. We further found that the disrupted NTS-NA connectivity was reversible, and was related to oxidative stress induced by augmented levels of NADPH oxidase-generated superoxide in the NTS. We conclude that depression of the cardiac vagal baroreflex induced by oxidative stress in the NTS in the context of neurogenic hypertension may be manifested in the form of dynamic alterations in the connectivity between the NTS and NA.

Detecting Blood–Brain Barrier Disruption Within Minimal Hemorrhage Following Transcranial Focused Ultrasound: A Correlation Study With Contrast-Enhanced MRI

Focused ultrasound combined with an intravascular ultrasound contrast agent can induce transient disruption of the blood–brain barrier, and the blood–brain barrier disruption can be detected by contrast‐enhanced MRI. There is, however, no study investigating the ability of various MR methods to detect focused ultrasound–induced blood–brain barrier disruption within minimal hemorrhage. Sonication was applied to 15 rat brains with four different doses of ultrasound contrast agent (0, 10, 30, or 50 μL/kg), and contrast‐enhanced T1‐weighted spin echo, gradient echo images, and longitudinal relaxation rate mapping along with effective transverse relaxation time–weighted and susceptibility‐weighted images were acquired. Volume‐of‐interest–based and threshold‐based analyses were performed to quantify the contrast enhancement, which was then correlated with the ultrasound contrast agent dose and with the amount of Evans blue extravasation. Both effective transverse relaxation time–weighted and susceptibility‐weighted images did not detect histology‐proved intracranial hemorrhage at 10 μL/kg, but MRI failed to detect mild intracranial hemorrhage at 30 μL/kg. All tested sequences showed detectable contrast enhancement increasing with ultrasound contrast agent dose. In correlating with Evans blue extravasation, the gradient echo sequence was slightly better than the spin echo sequence and was comparable to longitudinal relaxation rate mapping. In conclusion, both gradient echo and spin echo sequences were all reliable in indicating the degree of focused ultrasound–induced blood–brain barrier disruption within minimal hemorrhage. Magn Reson Med, 2011.

Ceftriaxone prevents the neurodegeneration and decreased neurogenesis seen in a Parkinson's disease rat model: An immunohistochemical and MRI study.

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsons disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD.

Pulse sequence and timing of contrast-enhanced MRI for assessing blood-brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage.

To optimize the timing of contrast‐enhanced magnetic resonance imaging (MRI) that best indicates blood–brain barrier (BBB) disruption induced by focused ultrasound (FUS) along with an ultrasound contrast agent (UCA) and to verify that the contrast‐enhanced spin‐echo MRI sequence can indicate the degree and location of BBB disruption in the presence of hemorrhage better than a gradient‐echo sequence.

Reduced encoding of diffusion spectrum imaging with cross-term correction

Diffusion Spectrum MRI (DSI) has been demonstrated to be capable of defining orientations of intersecting fibers accurately. However, the scanning procedure is overly time-consuming under the current sampling scheme. We developed a reduced encoding scheme of DSI and proved that decreasing the acquisition points to 62% is feasible by diffusion cross-term correction. We calculated the diffusion cross-term from the acquired data in the center of q space by assuming that image corresponding to any diffusion encoding direction suffers b values from diffusion gradients, imaging gradients and the cross-term between diffusion gradients and imaging gradients. The data in outer q space was then corrected with diffusion cross-term and filled by the data acquired with opposite diffusion gradients according to the geometric symmetry of diffusion anisotropy. Both ex-vivo crossing capillaries phantom and ex-vivo rat brain models showed that this method can decrease DSI acquisition time while preserving the patterns and orientations of probability density function.

Evaluation of structural connectivity changes in betel-quid chewers using generalized q-sampling MRI

RationaleBetel quid (BQ) is a common addictive substance in many Asian countries. However, few studies have focused on the influences of BQ on the brain. It remains unclear how BQ can affect structural brain abnormalities in BQ chewers.ObjectivesWe aimed to use generalized q-sampling imaging (GQI) to evaluate the impact of the neurological structure of white matter caused by BQ.MethodsThe study population comprised 16 BQ chewers, 15 tobacco and alcohol controls, and 17 healthy controls. We used GQI with voxel-based statistical analysis (VBA) to evaluate structural brain and connectivity abnormalities in the BQ chewers compared to the tobacco and alcohol controls and the healthy controls. Graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also performed to identify the structural network differences among the three groups.ResultsUsing GQI, we found increases in diffusion anisotropy in the right anterior cingulate cortex (ACC), the midbrain, the bilateral angular gyrus, the right superior temporal gyrus (rSTG), the bilateral superior occipital gyrus, the left middle occipital gyrus, the bilateral superior and inferior parietal lobule, and the bilateral postcentral and precentral gyrus in the BQ chewers when compared to the tobacco and alcohol controls and the healthy controls. In GTA and NBS analyses, we found more connections in connectivity among the BQ chewers, particularly in the bilateral anterior cingulum.ConclusionsOur results provided further evidence indicating that BQ chewing may lead to brain structure and connectivity changes in BQ chewers.

New Insights into the Developing Rabbit Brain Using Diffusion Tensor Tractography and Generalized q-Sampling MRI

The use of modern neuroimaging methods to characterize the complex anatomy of brain development at different stages reveals an enormous wealth of information in understanding this highly ordered process and provides clues to detect neurological and neurobehavioral disorders that have their origin in early structural and functional cerebral maturation. Non-invasive diffusion tensor magnetic resonance imaging (DTI) is able to distinguish cerebral microscopic structures, especially in the white matter regions. However, DTI is unable to resolve the complicated neural structure, i.e., the fiber crossing that is frequently observed during the maturation process. To overcome this limitation, several methods have been proposed. One such method, generalized q-sampling imaging (GQI), can be applied to a variety of datasets, including the single shell, multi-shell or grid sampling schemes that are believed to be able to resolve the complicated crossing fibers. Rabbits have been widely used for neurodevelopment research because they exhibit human-like timing of perinatal brain white matter maturation. Here, we present a longitudinal study using both DTI and GQI to demonstrate the changes in cerebral maturation of in vivo developing rabbit brains over a period of 40 weeks. Fractional anisotropy (FA) of DTI and generalized fractional anisotropy (GFA) of GQI indices demonstrated that the white matter anisotropy increased with age, with GFA exhibiting an increase in the hippocampus as well. Normalized quantitative anisotropy (NQA) of GQI also revealed an increase in the hippocampus, allowing us to observe the changes in gray matter as well. Regional and whole brain DTI tractography also demonstrated refinement in fiber pathway architecture with maturation. We concluded that DTI and GQI results were able to characterize the white matter anisotropy changes, whereas GQI provided further information about the gray matter hippocampus area. This developing rabbit brain DTI and GQI database could also be used for educational purposes and neuroscience investigations.