Effect of sedatives or anesthetics on the measurement of resting brain function in common marmosets.

Common marmosets are promising laboratory animals for the study of higher brain functions. Although there are many opportunities to use sedatives and anesthetics in resting brain function measurements in marmosets, their effects on the resting-state network remain unclear. In this study, the effects of sedatives or anesthetics such as midazolam, dexmedetomidine, co-administration of isoflurane and dexmedetomidine, propofol, alfaxalone, isoflurane, and sevoflurane on the resting brain function in common marmosets were evaluated using independent component analysis, dual regression analysis, and graph-theoretic analysis; and the sedatives or anesthetics suitable for the evaluation of resting brain function were investigated. The results show that network preservation tendency under light sedative with midazolam and dexmedetomidine is similar regardless of the type of target receptor. Moreover, alfaxalone, isoflurane, and sevoflurane have similar effects on resting state brain function, but only propofol exhibits different tendencies, as resting brain function is more preserved than it is following the administration of the other anesthetics. Co-administration of isoflurane and dexmedetomidine shows middle effect between sedatives and anesthetics.

Group Surrogate Data Generating Models and similarity quantification of multivariate time-series: A resting-state fMRI study.

Advancements in non-invasive brain analysis through novel approaches such as big data analytics and in silico simulation are essential for explaining brain function and associated pathologies. In this study, we extend the vector auto-regressive surrogate technique from a single multivariate time-series to group data using a novel Group Surrogate Data Generating Model (GSDGM). This methodology allowed us to generate biologically plausible human brain dynamics representative of a large human resting-state (rs-fMRI) dataset obtained from the Human Connectome Project. Simultaneously, we defined a novel similarity measure, termed the Multivariate Time-series Ensemble Similarity Score (MTESS). MTESS showed high accuracy and f-measure in subject identification, and it can directly compare the similarity between two multivariate time-series. We used MTESS to analyze both human and marmoset rs-fMRI data. Our results showed similarity differences between cortical and subcortical regions. We also conducted MTESS and state transition analysis between single and group surrogate techniques, and confirmed that a group surrogate approach can generate plausible group centroid multivariate time-series. Finally, we used GSDGM and MTESS for the fingerprint analysis of human rs-fMRI data, successfully distinguishing normal and outlier sessions. These new techniques will be useful for clinical applications and in silico simulation.

Influence of Diffusion Time and Temperature on Restricted Diffusion Signal: A Phantom Study.

PURPOSE: Diffusion MRI is a physical measurement method that quantitatively indicates the displacement of water molecules diffusing in voxels. However, there are insufficient data to characterize the diffusion process physically in a uniform structure such as a phantom. This study investigated the transitional relationship between structure scale, temperature, and diffusion time for simple restricted diffusion using a capillary phantom. METHODS: We performed diffusion-weighted pulsed-gradient stimulated-echo acquisition mode (STEAM) MRI with a 9.4 Tesla MRI system (Bruker BioSpin, Ettlingen, Germany) and a quadrature coil with an inner diameter of 86 mm (Bruker BioSpin). We measured the diffusion coefficients (radial diffusivity [RD]) of capillary plates (pore sizes 6, 12, 25, 50, and 100 µm) with uniformly restricted structures at various temperatures (10ºC, 20ºC, 30ºC, and 40ºC) and multiple diffusion times (12-800 ms). We evaluated the characteristics of scale, temperature, and diffusion time for restricted diffusion. RESULTS: The RD decayed and became constant depending on the structural scale. Diffusion coefficient fluctuations with temperature occurred mostly under conditions of a large structural scale and short diffusion time. We obtained data suggesting that temperature-dependent changes in the diffusion coefficients follow physical laws. CONCLUSION: No water molecules were observed outside the glass tubes in the capillary plates, and the capillary plates only reflected a restricted diffusion process within the structure.We experimentally evaluated the characteristics of simple restricted diffusion to reveal the transitional relationship of the diffusion coefficient with diffusion time, structure scale, and temperature through composite measurement.

Restricted diffusion characteristics in oscillating gradient spin echo with mesoscopic phantom.

In diffusion magnetic resonance imaging, oscillating gradient spin echo (OGSE) has an extremely short diffusion time if motion probing gradient (MPG) is applied to the waveform. Further, it can detect microstructural specificity. OGSE changes sensitivity to spin displacement velocity based on the MPG phase. The current study aimed to investigate the restricted diffusion characteristics of each OGSE waveform using the capillary phantom with various b-values, frequencies, and MPG phases. We performed OGSE (b-value = 300, 500, 800, 1200, 1600, and 2000 s/mm2) for the sine and cosine waveforms using the capillary phantom (6, 12, 25, 50, and 100 µm and free water) with a 9.4-T experimental magnetic resonance imaging system and a solenoid coil. We evaluated the axial and radial diffusivity (AD, RD) of each structure size. The output current of the MPG was assessed with an oscilloscope and analyzed with the gradient modulation power spectra by fast Fourier transform. In sine, the sidelobe spectrum was enhanced with increasing frequency, and the central spectrum slightly increased. The difference in RD was detected at 6 and 12 µm; however, it did not depend on the structure scale at 50 or 100 µm and free water. In cosine, the diffusion spectrum was enhanced, whereas the central spectrum decreased with increasing frequency. Both AD and RD in cosine had a frequency dependence, and AD and RD increased with a higher frequency regardless of structure size. AD and RD in either sine or cosine had no evident b-value dependence. We evaluated the OGSE-restricted diffusion characteristics. The measurements obtained diffusion information similar to the pulsed gradient spin echo. Hence, the cosine measurements indicated that a higher frequency could capture faster diffusion within the diffusion phenomena.

Identification of the reporter gene combination that shows high contrast for cellular level MRI.

Currently, we can label the certain cells by transducing specific genes, called reporter genes, and distinguish them from other cells. For example, fluorescent protein such as green fluorescence protein (GFP) is commonly used for cell labeling. However, fluorescent protein is difficult to observe in living animals. We can observe the reporter signals of the luciferin-luciferase system from the outside of living animals using in vivo imaging systems, although the resolution of this system is low. Therefore, in this study, we examined the reporter genes, which allowed the MRI-mediated observation of labeled cells in living animals. As a preliminary stage of animal study, we transduced some groups of plasmids that coded the protein that could take and store metal ions to the cell culture, added metal ions solutions, and measured their T1 or T2 relaxation values. Finally, we specified the best reporter gene combination for MRI, which was the combination of transferrin receptor, DMT1, and Ferritin-M6A for T1WI, and Ferritin-M6A for T2WI.

Commonality and variance of resting-state networks in common marmoset brains.

Animal models of brain function are critical for the study of human diseases and development of effective interventions. Resting-state network (RSN) analysis is a powerful tool for evaluating brain function and performing comparisons across animal species. Several studies have reported RSNs in the common marmoset (Callithrix jacchus; marmoset), a non-human primate. However, it is necessary to identify RSNs and evaluate commonality and inter-individual variance through analyses using a larger amount of data. In this study, we present marmoset RSNs detected using > 100,000 time-course image volumes of resting-state functional magnetic resonance imaging data with careful preprocessing. In addition, we extracted brain regions involved in the composition of these RSNs to understand the differences between humans and marmosets. We detected 16 RSNs in major marmosets, three of which were novel networks that have not been previously reported in marmosets. Since these RSNs possess the potential for use in the functional evaluation of neurodegenerative diseases, the data in this study will significantly contribute to the understanding of the functional effects of neurodegenerative diseases.

Distinct roles of amylin and oxytocin signaling in intrafamilial social behaviors at the medial preoptic area of common marmosets.

Calcitonin receptor (Calcr) and its brain ligand amylin in the medial preoptic area (MPOA) are found to be critically involved in infant care and social contact behaviors in mice. In primates, however, the evidence is limited to an excitotoxic lesion study of the Calcr-expressing MPOA subregion (cMPOA) in a family-living primate species, the common marmoset. The present study utilized pharmacological manipulations of the cMPOA and shows that reversible inactivation of the cMPOA abolishes infant-care behaviors in sibling marmosets without affecting other social or non-social behaviors. Amylin-expressing neurons in the marmoset MPOA are distributed in the vicinity of oxytocin neurons in the anterior paraventricular nucleus of the hypothalamus. While amylin infusion facilitates infant carrying selectively, an oxytocin's inverse agonist, atosiban, reduces physical contact with non-infant family members without grossly affecting infant care. These data suggest that the amylin and oxytocin signaling mediate intrafamilial social interactions in a complementary manner in marmosets.

Multi-modal brain magnetic resonance imaging database covering marmosets with a wide age range.

Magnetic resonance imaging (MRI) is a non-invasive neuroimaging technique that is useful for identifying normal developmental and aging processes and for data sharing. Marmosets have a relatively shorter life expectancy than other primates, including humans, because they grow and age faster. Therefore, the common marmoset model is effective in aging research. The current study investigated the aging process of the marmoset brain and provided an open MRI database of marmosets across a wide age range. The Brain/MINDS Marmoset Brain MRI Dataset contains brain MRI information from 216 marmosets ranging in age from 1 and 10 years. At the time of its release, it is the largest public dataset in the world. It also includes multi-contrast MRI images. In addition, 91 of 216 animals have corresponding high-resolution ex vivo MRI datasets. Our MRI database, available at the Brain/MINDS Data Portal, might help to understand the effects of various factors, such as age, sex, body size, and fixation, on the brain. It can also contribute to and accelerate brain science studies worldwide.

Effects of chronic caffeine intake and withdrawal on neural activity assessed via resting-state functional magnetic resonance imaging in mice.

Caffeine is a psychoactive substance that not only improves wakefulness, but also slows the cognitive decline caused by aging. However, at present, there are no reports about the effects of caffeine withdrawal, including headaches and changes in brain functional networks (nerve activity). Headache may occur approximately 24 h after discontinuing caffeine intake in chronic caffeine drinkers. The current study aimed to examine the brain functional activity via resting-state functional magnetic resonance imaging in chronically caffeinated and decaffeinated groups to investigate changes in brain activity caused by caffeine. C57BL/6J mice were included in the analysis, and they underwent 9.4-T ultrahigh-field magnetic resonance imaging. The mice were classified into the control, chronic caffeinated, and caffeine withdrawal grsoups. Mice were divided into three groups: 1) not exposed to caffeine (control); 2) treated with caffeine at a concentration of 0.3 mg/mL for 4 weeks (chronic caffeinated); and 3) treated as before with caffeine and withdrawn from caffeine for 24 h. After the three groups were examined, functional connectivity matrices were calculated using brain imaging analysis tools, and independent component analysis was performed. The results showed that caffeine administration activated neural activity areas in the stress response system. Furthermore, 24h after caffeine withdrawal, the results showed an increase in pain-related neural activity. In addition, caffeine administration was shown to activate the dentate gyrus, one of the hippocampal regions, and to decrease the neural activity in the olfactory bulb and anterior cingulate cortex. In the current research, the neural activity of specific brain regions changed after chronic caffeine administration and withdrawal.

Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter.

Alzheimer's disease (AD) is the leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the AD's molecular basis from studies on various mouse models, it has been suffered from evolutionary species differences. Here, we report generation of a non-human primate (NHP), common marmoset model ubiquitously expressing Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. The transgene integration of generated two transgenic marmosets (TG1&TG2) was thoroughly investigated by genomic PCR, whole-genome sequencing, and fluorescence in situ hybridization. By reprogramming, we confirmed the validity of transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging analysis, including in the entorhinal cortex and hippocampus. In immunohistochemistry, we detected increased Aß plaque-like structures in TG1 brain at 7 years old, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish an NHP AD model. Although the transgenesis approach alone seemed not sufficient to fully recapitulate AD in NHPs, it may be beneficial for drug development and further disease modeling by combination with other genetically engineered models and disease-inducing approaches.

MR Imaging Properties of ex vivo Common Marmoset Brain after Formaldehyde Fixation.

PURPOSE: Ex vivo brains have different MRI properties than in vivo brains because of chemical changes caused by fixative solutions, which change the signal intensity and/or tissue contrast on MR images. In this study, we investigated and compared the MRI properties of in vivo and ex vivo brains. METHODS: Using a Bruker 9.4T experimental scanner unit for animals (Biospin GmbH, Ettlingen, Germany), we performed this study on the common marmoset. We measured the relaxation and diffusion values in the white matter and cortex of common marmosets and compared these values between in vivo brains (n = 20) and ex vivo brains (n = 20). Additionally, we observed the relationship between the tissue fixation duration and MRI properties by imaging a brain that underwent long-term fixation in a preliminary examination (n = 1). RESULTS: The T1 values of ex vivo brains were decreased compared with those of in vivo brains; however, there were no significant difference in the T2 and T2* values of in vivo and ex vivo brains. Axial, radial, and mean diffusivity values of ex vivo brains decreased to approximately 65% and 52% of those of in vivo brains in the cortex and white matter, respectively. Conversely, fractional anisotropy values were not significantly different between in vivo and ex vivo brains. CONCLUSION: The T1 values and diffusion coefficient values of the ex vivo brains were strikingly different than those of the in vivo brains. Conversely, there were no significant changes in the T2, T2* or fractional anisotropy values. Altogether, the dehydration caused by tissue fixation and the reduction in brain temperature were involved in changing the relaxation and diffusion coefficient values. Here, it was difficult to specify all factors causing these changes. Further detailed study is needed to examine changes in MRI properties.

Semiquantitative Evaluation of Muscle Repair by Diffusion Tensor Imaging in Mice.

Muscle injury is one of the most common traumas in orthopedic and sports medicine. However, there are only a few treatment options with marginal clinical benefits for this condition. Muscle repair after injury involves multiple and complex processes, such as the inflammation phase, regeneration phase, and remodeling phase. To develop a treatment modality and to examine the efficacy of novel interventions and agents for patients with muscle injuries, it is essential to establish a reliable and sensitive method to monitor the changes in muscle structure and status during muscle repair. Diffusion-weighted magnetic resonance imaging has been widely used to assess the diffusivity of water molecules in tissue. When it is used in combination with diffusion tensor imaging (DTI), the microstructure of muscle tissue can be indirectly depicted. In the present study, we evaluated the time-course changes in the diffusivity and anisotropy in muscles by DTI and histology after injury in mice. We found that the diffusivity and anisotropy exhibit distinct kinetics during muscle repair and that these kinetics were significantly altered in mutant mice with a defect in muscle regeneration. Our data show that muscle repair processes can be readily evaluated and monitored by DTI technique and suggest that DTI can be clinically applied for assessing muscle injury and repair in humans. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.