Structural MRI analysis of age-related changes and sex differences in marmoset brain volume.

The field of aging biology, which aims to extend healthy lifespans and prevent age-related diseases, has turned its focus to the Callithrix jacchus (common marmoset) to understand the aging process better. This study utilized magnetic resonance imaging (MRI) to non-invasively analyze the brains of 216 marmosets, investigating age-related changes in brain structure; the relationship between body weight and brain volume; and potential differences between males and females. The key findings revealed that, similar to humans, Callithrix jacchus experiences a reduction in total intracranial volume, cortex, subcortex, thalamus, and cingulate volumes as they age, highlighting site-dependent changes in brain tissue. Notably, the study also uncovered sex differences in cerebellar volume. These insights into the structural connectivity and volumetric changes in the marmoset brain throughout aging contribute to accumulating valuable knowledge in the field, promising to inform future aging research and interventions for enhancing healthspan.

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.

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.

Formation Processes of a Solid Electrolyte Interphase at a Silicon/Sulfide Electrolyte Interface in a Model All-Solid-State Li-Ion Battery.

Understanding the electrochemical reactions at the interface between a Si anode and a solid sulfide electrolyte is essential in improving the cycle stabilities of Si anodes in all-solid-state batteries (ASSBs). Highly dense Si films with very low roughnesses of <1 nm were fabricated at room temperature via cathodic arc plasma deposition, which led to the formation of a Si/sulfide electrolyte model interface. Li (de)alloying through the model interface hardly occurred during the first cycle, whereas it proceeded stably in subsequent cycles. Hard X-ray photoelectron spectroscopy and neutron reflectometry directly revealed that the reduction or oxidation of the interfacial component or Li3PS4 electrolyte occurred during the first cycle. Consequently, an interfacial layer with a thickness of 13 nm and primarily composed of Li2S, SiS2, and P2S5 glasses was formed during the first cycle. The interfacial layer acted as a Li-conductive, electron-insulating solid electrolyte interphase (SEI) that provided reversible (de)lithiation. Our model interface directly demonstrates the electrochemical reaction processes at the Si/Li3PS4 interface and provides insights into the structures and electrochemical properties of SEIs to activate the (de)lithiation of Si anodes using a sulfide electrolyte.

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.

Non-lesional white matter changes depicted by q-space diffusional MRI correlate with clinical disabilities in multiple sclerosis.

BACKGROUND: We previously developed an optimized q-space diffusional MRI technique (normalized leptokurtic diffusion [NLD] map) to delineate the demyelinated lesions of multiple sclerosis (MS) patients. Herein, we evaluated the utility of NLD maps to discern the white matter abnormalities in normal-appearing white matter (NAWM) and the abnormalities' possible associations with physical and cognitive disabilities in MS. METHODS: We conducted a retrospective observational study of MS patients treated at our hospital (Jan. 2012 to Dec. 2022). Clinical and MRI data were collected; Processing Speed Test (PST) data were obtained when possible. For a quantitative analysis of the NLD maps, we calculated the NLD index as GVROI/GVREF, where GV is a mean grayscale value in the regions of interest (ROIs) and the reference area (REF; cerebrospinal fluid). RESULTS: One hundred-one individuals with MS were included. The lower corpus callosum and non-lesional WM NLD index were associated with worse Expanded Disability Status Scale (EDSS) and PST scores. The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly reduced in progressive MS compared to relapsing-remitting MS. We categorized MS severity as moderate/severe (EDSS score ≥ 4 points) and mild (EDSS score < 4 points). The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly lower in the moderate/severe MS group compared to the mild MS group. CONCLUSION: The NLD map revealed abnormalities in the non-lesional white matter, providing valuable insights for evaluating manifestations in MS patients.

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.

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.

A shift of brain network hub after spinal cord injury.

Background: Spinal cord injury (SCI) causes severe sequelae and significant social loss, depending on the extent of the damage. Most previous studies have focused on the pathology of the spinal cord to develop treatments for SCI. However, it is now known that the brain, which is not directly damaged, also undergoes morphological changes after spinal cord injury, which could affect natural recovery and treatment. In recent years, magnetic resonance imaging (MRI) has been developed to analyze functional changes in the brain. Resting-state functional MRI (rsfMRI), which captures brain activity at rest, can calculate functional connections between brain areas and identify central hubs by network analysis. Purpose: We aim to investigate functional connectivity in the brain using rsfMRI after SCI and to determine how brain-network main hubs change over time. Methods: We evaluated rsfMRI in 10 mice of the contusional SCI model and calculated connectivity using graph theory. We evaluated "centrality," a representative parameter of network analysis. The subtype of centrality was degree centrality, which indicates the hub function of a single area. The five times of rsfMRI were performed in each individual mouse: before injury and at 1, 3, 7, and 14 weeks post-injury. Results: Before the injury, the degree centralities of the primary and secondary motor cortex were high, suggesting that these motor cortices served as main hubs for motor function. After SCI, the hub function of the motor cortices decreased by 14 weeks. In contrast, hub function in the external capsule and the putamen comparatively increased with time after injury, suggesting that the extrapyramidal/subcortical system, which runs the ventral side of the spinal cord and remains after injury in this model, becomes dominant. Conclusion: We demonstrated the shift of the brain network hub after SCI. The results of this study provide basic information for understanding brain network changes after SCI and would be useful for treatment selection and evaluation of its efficacy in SCI patients.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

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.

The Brain/MINDS Marmoset Connectivity Resource: An open-access platform for cellular-level tracing and tractography in the primate brain.

The primate brain has unique anatomical characteristics, which translate into advanced cognitive, sensory, and motor abilities. Thus, it is important that we gain insight on its structure to provide a solid basis for models that will clarify function. Here, we report on the implementation and features of the Brain/MINDS Marmoset Connectivity Resource (BMCR), a new open-access platform that provides access to high-resolution anterograde neuronal tracer data in the marmoset brain, integrated to retrograde tracer and tractography data. Unlike other existing image explorers, the BMCR allows visualization of data from different individuals and modalities in a common reference space. This feature, allied to an unprecedented high resolution, enables analyses of features such as reciprocity, directionality, and spatial segregation of connections. The present release of the BMCR focuses on the prefrontal cortex (PFC), a uniquely developed region of the primate brain that is linked to advanced cognition, including the results of 52 anterograde and 164 retrograde tracer injections in the cortex of the marmoset. Moreover, the inclusion of tractography data from diffusion MRI allows systematic analyses of this noninvasive modality against gold-standard cellular connectivity data, enabling detection of false positives and negatives, which provide a basis for future development of tractography. This paper introduces the BMCR image preprocessing pipeline and resources, which include new tools for exploring and reviewing the data.

Local and long-distance organization of prefrontal cortex circuits in the marmoset brain.

The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections' local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain.

The Japan Monkey Centre Primates Brain Imaging Repository of high-resolution postmortem magnetic resonance imaging: The second phase of the archive of digital records.

A comparison of neuroanatomical features of the brain between humans and our evolutionary relatives, nonhuman primates, is key to understanding the human brain system and the neural basis of mental and neurological disorders. Although most comparative MRI studies of human and nonhuman primate brains have been based on brains of primates that had been used as subjects in experiments, it is essential to investigate various species of nonhuman primates in order to elucidate and interpret the diversity of neuroanatomy features among humans and nonhuman primates. To develop a research platform for this purpose, it is necessary to harmonize the scientific contributions of studies with the standards of animal ethics, animal welfare, and the conservation of brain information for long-term continuation of the field. In previous research, we first developed a gated data-repository of anatomical images obtained using 9.4-T ex vivo MRI of postmortem brain samples from 12 nonhuman primate species, and which are stored at the Japan Monkey Centre. In the present study, as a second phase, we released a collection of T2-weighted images and diffusion tensor images obtained in nine species: white-throated capuchin, Bolivian squirrel monkey, stump-tailed macaque, Tibet monkey, Sykes' monkey, Assamese macaque, pig-tailed macaque, crested macaque, and chimpanzee. Our image repository should facilitate scientific discoveries in the field of comparative neuroscience. This repository can also promote animal ethics and animal welfare in experiments with nonhuman primate models by optimizing methods for in vivo and ex vivo MRI scanning of brains and supporting veterinary neuroradiological education. In addition, the repository is expected to contribute to conservation, preserving information about the brains of various primates, including endangered species, in a permanent digital form.

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.

A Novel Rat Model of Embolic Cerebral Ischemia Using a Cell-Implantable Radiopaque Hydrogel Microfiber.

The failure of neuroprotective treatment-related clinical trials, including stem cell therapies, may be partially due to a lack of suitable animal models. We have developed a stem cell-implantable radiopaque hydrogel microfiber that can survive for a long time in vivo. The microfiber is made of barium alginate hydrogel containing zirconium dioxide, fabricated in a dual coaxial laminar flow microfluidic device. We aimed to develop a novel focal stroke model using this microfiber. Using male Sprague-Dawley rats (n=14), a catheter (inner diameter, 0.42 mm; outer diameter, 0.55 mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel microfiber (diameter, 0.4 mm; length, 1 mm) was advanced through the catheter by slow injection of heparinized physiological saline to establish local occlusion. Both 9.4-T magnetic resonance imaging at 3 and 6 h and 2% 2,3,5-triphenyl tetrazolium chloride staining at 24 h after stroke model creation were performed. Neurological deficit score and body temperature were measured. The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized in all rats. Median operating time was 4 min (interquartile range [IQR], 3-8 min). Mean infarct volume was 388 mm3 (IQR, 354-420 mm3) at 24 h after occlusion. No infarction of the thalamus or hypothalamus was seen. Body temperature did not change significantly over time (P = 0.204). However, neurological deficit scores before and at 3, 6, and 24 h after model creation differed significantly (P < 0.001). We present a novel rat model of focal infarct restricted to the middle cerebral artery territory using a radiopaque hydrogel microfiber positioned under fluoroscopic guidance. By comparing the use of stem cell-containing versus non-containing fibers in this stroke model, it would be possible to determine the efficacy of "pure" cell transplantation in treating stroke.

Developmental changes in brain activity of heterozygous Scn1a knockout rats.

Introduction: Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy characterized by an age-dependent evolution of drug-resistant seizures and poor developmental outcomes. Functional impairment of gamma-aminobutyric acid (GABA)ergic interneurons due to loss-of-function mutation of SCN1A is currently considered the main pathogenesis. In this study, to better understand the age-dependent changes in the pathogenesis of DS, we characterized the activity of different brain regions in Scn1a knockout rats at each developmental stage. Methods: We established an Scn1a knockout rat model and examined brain activity from postnatal day (P) 15 to 38 using a manganese-enhanced magnetic resonance imaging technique (MEMRI). Results: Scn1a heterozygous knockout (Scn1a +/-) rats showed a reduced expression of voltage-gated sodium channel alpha subunit 1 protein in the brain and heat-induced seizures. Neural activity was significantly higher in widespread brain regions of Scn1a +/- rats than in wild-type rats from P19 to P22, but this difference did not persist thereafter. Bumetanide, a Na+-K+-2Cl- cotransporter 1 inhibitor, mitigated hyperactivity to the wild-type level, although no change was observed in the fourth postnatal week. Bumetanide also increased heat-induced seizure thresholds of Scn1a +/- rats at P21. Conclusions: In Scn1a +/- rats, neural activity in widespread brain regions increased during the third postnatal week, corresponding to approximately 6 months of age in humans, when seizures most commonly develop in DS. In addition to impairment of GABAergic interneurons, the effects of bumetanide suggest a possible contribution of immature type A gamma-aminobutyric acid receptor signaling to transient hyperactivity and seizure susceptibility during the early stage of DS. This hypothesis should be addressed in the future. MEMRI is a potential technique for visualizing changes in basal brain activity in developmental and epileptic encephalopathies.

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.

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.