Squirrel Monkey Brain Research Articles

Detection and characterization of resting state functional networks in squirrel monkey brain.

Resting-state fMRI based on analyzing BOLD signals is widely used to derive functional networks in the brain and how they alter during disease or injury conditions. Resting-state networks can also be used to study brain functional connectomes across species, which provides insights into brain evolution. The squirrel monkey (SM) is a non-human primate (NHP) that is widely used as a preclinical model for experimental manipulations to understand the organization and functioning of the brain. We derived resting-state networks from the whole brain of anesthetized SMs using Independent Component Analysis of BOLD acquisitions. We detected 15 anatomically constrained resting-state networks localized in the cortical and subcortical regions as well as in the white-matter. Networks encompassing visual, somatosensory, executive control, sensorimotor, salience and default mode regions, and subcortical networks including the Hippocampus-Amygdala, thalamus, basal-ganglia and brainstem region correspond well with previously detected networks in humans and NHPs. The connectivity pattern between the networks also agrees well with previously reported seed-based resting-state connectivity of SM brain. This study demonstrates that SMs share remarkable homologous network organization with humans and other NHPs, thereby providing strong support for their suitability as a translational animal model for research and additional insight into brain evolution across species.

Optimization of a quadrature birdcage coil for functional imaging of squirrel monkey brain at 9.4T

A quadrature transmit/receive birdcage coil was optimized for squirrel monkey functional imaging at the high field of 9.4 T. The coil length was chosen to gain maximum coil efficiency/signal-to-noise ratio (SNR) and meanwhile provide enough homogenous RF field in the whole brain area. Based on the numerical simulation results, a 16-rung high-pass birdcage coil with the optimal length of 9 cm was constructed and evaluated on phantom and in vivo experiments. Compared to a general-purpose non-optimized coil, it exhibits approximately 25% in vivo SNR improvement. In addition to the volume coil, details about how to design and construct the associated animal preparation system were provided.

Deep learning reveals untapped information for local white-matter fiber reconstruction in diffusion-weighted MRI

PurposeDiffusion-weighted magnetic resonance imaging (DW-MRI) is of critical importance for characterizing in-vivo white matter. Models relating microarchitecture to observed DW-MRI signals as a function of diffusion sensitization are the lens through which DW-MRI data are interpreted. Numerous modern approaches offer opportunities to assess more complex intra-voxel structures. Nevertheless, there remains a substantial gap between intra-voxel estimated structures and ground truth captured by 3-D histology. MethodsHerein, we propose a novel data-driven approach to model the non-linear mapping between observed DW-MRI signals and ground truth structures using a sequential deep neural network regression using residual block deep neural network (ResDNN). Training was performed on two 3-D histology datasets of squirrel monkey brains and validated on a third. A second validation was performed using scan-rescan datasets of 12 subjects from Human Connectome Project. The ResDNN was compared with multiple micro-structure reconstruction methods and super resolved-constrained spherical deconvolution (sCSD) in particular as baseline for both the validations. ResultsAngular correlation coefficient (ACC) is a correlation/similarity measure and can be interpreted as accuracy when compared with a ground truth. The median ACC of ResDNN is 0.82 and median ACC's of different variants of CSD are 0.75, 0.77, 0.79. The mean, median and std. of ResDNN & sCSD ACC across 12 subjects from HCP are 0.74, 0.88, 0.31 and 0.61, 0.71, 0.31 respectively. ConclusionThis work highlights the ability of deep learning to capture linkages between ex-vivo ground truth data with feasible MRI sequences. The data-driven approach is applicable to human in-vivo data and results in intriguingly high reproducibility of orientation structure.

LEARNING 3D WHITE MATTER MICROSTRUCTURE FROM 2D HISTOLOGY.

Histological analysis is typically the gold standard for validating measures of tissue microstructure derived from magnetic resonance imaging (MRI) contrasts. However, most histological investigations are inherently 2-dimensional (2D), due to increased field-of-view, higher in-plane resolutions, ease of acquisition, decreased costs, and a large number of available contrasts compared to 3-dimensional (3D) analysis. Because of this, it would be of great interest to be able to learn the 3D tissue microstructure from 2D histology. In this study, we use diffusion MRI (dMRI) of a squirrel monkey brain and corresponding myelin stained sections in combination with a convolution neural network to learn the relationship between the 3D diffusion estimated axonal fiber orientation distributions and the 2D myelin stain. We find that we are able to estimate the 3D fiber distribution with moderate to high angular agreement with the ground truth (median angular correlation coefficients of 0.48 across the unseen slices). This network could be used to validate dMRI neuronal structural measurements in 3D, even if only 2D histology is available for validation. Generalization is possible to transfer this network to human stained sections to infer the 3D fiber distribution at resolutions currently unachievable with dMRI, which would allow diffusion fiber tractography at unprecedented resolutions. We envision the use of similar networks to learn other 3D microstructural measures from an array of potential common 2D histology contrasts.

Histologically derived fiber response functions for diffusion MRI vary across white matter fibers-An ex vivo validation study in the squirrel monkey brain.

Understanding the relationship between the diffusion-weighted MRI signal and the arrangement of white matter fibers is fundamental for accurate voxel-wise reconstruction of the fiber orientation distribution (FOD) and subsequent fiber tractography. Spherical deconvolution reconstruction techniques model the diffusion signal as the convolution of the FOD with a response function that represents the signal profile of a single fiber orientation. Thus, given the signal and a fiber response function, the FOD can be estimated in every imaging voxel by deconvolution. However, the selection of the appropriate response function remains relatively under-studied, and requires further validation. In this work, using 3D histologically defined FODs and the corresponding diffusion signal from three ex vivo squirrel monkey brains, we derive the ground truth response functions. We find that the histologically derived response functions differ from those conventionally used. Next, we find that response functions statistically vary across brain regions, which suggests that the practice of using the same kernel throughout the brain is not optimal. We show that different kernels lead to different FOD reconstructions, which in turn can lead to different tractography results depending on algorithmic parameters, with large variations in the accuracy of resulting reconstructions. Together, these results suggest there is room for improvement in estimating and understanding the relationship between the diffusion signal and the underlying FOD.

Anatomical accuracy of standard-practice tractography algorithms in the motor system - A histological validation in the squirrel monkey brain

For two decades diffusion fiber tractography has been used to probe both the spatial extent of white matter pathways and the region to region connectivity of the brain. In both cases, anatomical accuracy of tractography is critical for sound scientific conclusions. Here we assess and validate the algorithms and tractography implementations that have been most widely used - often because of ease of use, algorithm simplicity, or availability offered in open source software. Comparing forty tractography results to a ground truth defined by histological tracers in the primary motor cortex on the same squirrel monkey brains, we assess tract fidelity on the scale of voxels as well as over larger spatial domains or regional connectivity. No algorithms are successful in all metrics, and, in fact, some implementations fail to reconstruct large portions of pathways or identify major points of connectivity. The accuracy is most dependent on reconstruction method and tracking algorithm, as well as the seed region and how this region is utilized. We also note a tremendous variability in the results, even though the same MR images act as inputs to all algorithms. In addition, anatomical accuracy is significantly decreased at increased distances from the seed. An analysis of the spatial errors in tractography reveals that many techniques have trouble properly leaving the gray matter, and many only reveal connectivity to adjacent regions of interest. These results show that the most commonly implemented algorithms have several shortcomings and limitations, and choices in implementations lead to very different results. This study should provide guidance for algorithm choices based on study requirements for sensitivity, specificity, or the need to identify particular connections, and should serve as a heuristic for future developments in tractography.

A Web-Based Atlas Combining MRI and Histology of the Squirrel Monkey Brain.

The squirrel monkey (Saimiri sciureus) is a commonly-used surrogate for humans in biomedical research. In the neuroimaging community, MRI and histological atlases serve as valuable resources for anatomical, physiological, and functional studies of the brain; however, no digital MRI/histology atlas is currently available for the squirrel monkey. This paper describes the construction of a web-based multi-modal atlas of the squirrel monkey brain. The MRI-derived information includes anatomical MRI contrast (i.e., T2-weighted and proton-density-weighted) and diffusion MRI metrics (i.e., fractional anisotropy and mean diffusivity) from data acquired both in vivo and ex vivo on a 9.4 Tesla scanner. The histological images include Nissl and myelin stains, co-registered to the corresponding MRI, allowing identification of cyto- and myelo-architecture. In addition, a bidirectional neuronal tracer, biotinylated dextran amine (BDA) was injected into the primary motor cortex, enabling highly specific identification of regions connected to the injection location. The atlas integrates the results of common image analysis methods including diffusion tensor imaging glyphs, labels of 57 white-matter tracts identified using DTI-tractography, and 18 cortical regions of interest identified from Nissl-revealed cyto-architecture. All data are presented in a common space, and all image types are accessible through a web-based atlas viewer, which allows visualization and interaction of user-selectable contrasts and varying resolutions. By providing an easy to use reference system of anatomical information, our web-accessible multi-contrast atlas forms a rich and convenient resource for comparisons of brain findings across subjects or modalities. The atlas is called the Combined Histology-MRI Integrated Atlas of the Squirrel Monkey (CHIASM). All images are accessible through our web-based viewer ( https://chiasm.vuse.vanderbilt.edu /), and data are available for download at ( https://www.nitrc.org/projects/smatlas/ ).

The VALiDATe29 MRI Based Multi-Channel Atlas of the Squirrel Monkey Brain.

We describe the development of the first digital atlas of the normal squirrel monkey brain and present the resulting product, VALiDATe29. The VALiDATe29 atlas is based on multiple types of magnetic resonance imaging (MRI) contrast acquired on 29 squirrel monkeys, and is created using unbiased, nonlinear registration techniques, resulting in a population-averaged stereotaxic coordinate system. The atlas consists of multiple anatomical templates (proton density, T1, and T2* weighted), diffusion MRI templates (fractional anisotropy and mean diffusivity), and ex vivo templates (fractional anisotropy and a structural MRI). In addition, the templates are combined with histologically defined cortical labels, and diffusion tractography defined white matter labels. The combination of intensity templates and image segmentations make this atlas suitable for the fundamental atlas applications of spatial normalization and label propagation. Together, this atlas facilitates 3D anatomical localization and region of interest delineation, and enables comparisons of experimental data across different subjects or across different experimental conditions. This article describes the atlas creation and its contents, and demonstrates the use of the VALiDATe29 atlas in typical applications. The atlas is freely available to the scientific community.

High-resolution functional MRI identified distinct global intrinsic functional networks of nociceptive posterior insula and S2 regions in squirrel monkey brain

Numerous functional imaging and electrophysiological studies in humans and animals indicate that the two contiguous areas of secondary somatosensory cortex (S2) and posterior insula (pIns) are core regions in nociceptive processing and pain perception. In this study, we tested the hypothesis that the S2-pIns connection serves as a hub for connecting distinct sensory and affective nociceptive processing networks in the squirrel monkey brain. At 9.4T, we first mapped the brain regions that respond to nociceptive heat stimuli with high-resolution fMRI, and then used seed-based resting-state fMRI (rsfMRI) analysis to delineate and refine the global intrinsic functional connectivity circuits of the proximal S2 and pIns regions. In each subject, nociceptive (47.5°C) heat-evoked fMRI activations were detected in many brain regions, including primary somatosensory (S1), S2, pIns, area 7b, anterior cingulate cortex (ACC), primary motor cortex, prefrontal cortex, supplementary motor area, thalamus, and caudate. Using the heat-evoked fMRI activation foci in S2 and pIns as the seeds, voxel-wise whole-brain resting-state functional connectivity (rsFC) analysis revealed strong functional connections between contralateral S2 and pIns, as well as their corresponding regions in the ipsilateral hemisphere. Spatial similarity and overlap analysis identified each region as part of two distinct intrinsic functional networks with 7% overlap: sensory S2-S1-area 7b and affective pIns-ACC-PCC networks. Moreover, a high degree of overlap was observed between the combined rsFC maps of nociceptive S2 and pIns regions and the nociceptive heat-evoked activation map. In summary, our study provides evidence for the existence of two distinct intrinsic functional networks for S2 and pIns nociceptive regions, and these two networks are joined via the S2-pIns connection. Brain regions that are involved in processing nociceptive inputs are also highly interconnected at rest. The presence of robust and distinct S1-S2-area 7b and pIns-ACC-PCC rsFC networks under anesthesia underscores their fundamental roles in processing nociceptive information.

Reproducibility and variation of diffusion measures in the squirrel monkey brain, in vivo and ex vivo

PurposeAnimal models are needed to better understand the relationship between diffusion MRI (dMRI) and the underlying tissue microstructure. One promising model for validation studies is the common squirrel monkey, Saimiri sciureus. This study aims to determine (1) the reproducibility of in vivo diffusion measures both within and between subjects; (2) the agreement between in vivo and ex vivo data acquired from the same specimen and (3) normal diffusion values and their variation across brain regions. MethodsData were acquired from three healthy squirrel monkeys, each imaged twice in vivo and once ex vivo. Reproducibility of fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) was assessed, and normal values were determined both in vivo and ex vivo. ResultsThe calculated coefficients of variation (CVs) for both intra-subject and inter-subject MD were below 10% (low variability) while FA had a wider range of CVs, 2–14% intra-subject (moderate variability), and 3–31% inter-subject (high variability). MD in ex vivo tissue was lower than in vivo (30%–50% decrease), while FA values increased in all regions (30–39% increase). The mode of angular differences between in vivo and ex vivo PEVs was 12 degrees. ConclusionThis study characterizes the diffusion properties of the squirrel monkey brain and serves as the groundwork for using the squirrel monkey, both in vivo and ex vivo, as a model for diffusion MRI studies.

Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease

The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of 3H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors.

Integrating histology and MRI in the first digital brain of common squirrel monkey, Saimiri sciureus.

This effort is a continuation of development of a digital brain atlas of the common squirrel monkey, Saimiri sciureus, a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. Here, we present the integration of histology with multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. The central concept of this work is to use block face photography to establish an intermediate common space in coordinate system which preserves the high resolution in-plane resolution of histology while enabling 3-D correspondence with MRI. In vivo MRI acquisitions include high resolution T2 structural imaging (300 µm isotropic) and low resolution diffusion tensor imaging (600 um isotropic). Ex vivo MRI acquisitions include high resolution T2 structural imaging and high resolution diffusion tensor imaging (both 300 µm isotropic). Cortical regions were manually annotated on the co-registered volumes based on published histological sections in-plane. We describe mapping of histology and MRI based data of the common squirrel monkey and construction of a viewing tool that enable online viewing of these datasets. The previously descried atlas MRI is used for its deformation to provide accurate conformation to the MRI, thus adding information at the histological level to the MRI volume. This paper presents the mapping of single 2D image slice in block face as a proof of concept and this can be extended to map the atlas space in 3D coordinate system as part of the future work and can be loaded to an XNAT system for further use.

A brain MRI atlas of the common squirrel monkey, Saimiri sciureus.

The common squirrel monkey, Saimiri sciureus, is a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. It is one of the most commonly used South American primates in biomedical research. Unlike its Old World macaque cousins, no digital atlases have described the organization of the squirrel monkey brain. Here, we present a multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. In vivo MRI acquisitions include T2 structural imaging and diffusion tensor imaging. Ex vivo MRI acquisitions include T2 structural imaging and diffusion tensor imaging. Cortical regions were manually annotated on the co-registered volumes based on published histological sections.

Evaluation of σ-1 Receptor Radioligand 18F-FTC-146 in Rats and Squirrel Monkeys Using PET

The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation. The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum. Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents. Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

Validation of DTI tractography-based measures of primary motor area connectivity in the squirrel monkey brain.

Diffusion tensor imaging (DTI) tractography provides noninvasive measures of structural cortico-cortical connectivity of the brain. However, the agreement between DTI-tractography-based measures and histological ‘ground truth’ has not been quantified. In this study, we reconstructed the 3D density distribution maps (DDM) of fibers labeled with an anatomical tracer, biotinylated dextran amine (BDA), as well as DTI tractography-derived streamlines connecting the primary motor (M1) cortex to other cortical regions in the squirrel monkey brain. We evaluated the agreement in M1-cortical connectivity between the fibers labeled in the brain tissue and DTI streamlines on a regional and voxel-by-voxel basis. We found that DTI tractography is capable of providing inter-regional connectivity comparable to the neuroanatomical connectivity, but is less reliable measuring voxel-to-voxel variations within regions.

Single oral doses of (±) 3,4-methylenedioxymethamphetamine (‘Ecstasy’) produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations

Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.

Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys

Several classes of drugs bind to the dopamine transporter (DAT) with high affinity, but some are weaker positive reinforcers than cocaine, suggesting that affinity for and occupancy of the DAT is not the only determinant of a drug's reinforcing effectiveness. Other factors such as the rate of onset have been positively and strongly correlated with the reinforcing effects of DAT inhibitors in nonhuman primates. In the current studies, we examined the effects of acute systemic administration of cocaine and three cocaine analogs (RTI-150, RTI-177, and RTI-366) on binding to DAT in squirrel monkey brain using positron emission tomography (PET) neuroimaging. During the PET scan, we also measured drug effects on dopamine (DA) levels in the caudate using in vivo microdialysis. In general, our results suggest a lack of concordance between drug occupancy at DAT and changes in DA levels. These studies also indicate that acute cocaine administration decreases the availability of plasma membrane DAT for binding, even after cocaine is no longer blocking DA uptake as evidence by a return to basal DA levels.

Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

Squirrel monkeys (Saimiri sciureus) were infected experimentally with the agent of classical bovine spongiform encephalopathy (BSE). Two to four years later, six of the monkeys developed alterations in interactive behaviour and cognition and other neurological signs typical of transmissible spongiform encephalopathy (TSE). At necropsy examination, the brains from all of the monkeys showed pathological changes similar to those described in variant Creutzfeldt-Jakob disease (vCJD) of man, except that the squirrel monkey brains contained no PrP-amyloid plaques typical of that disease. Constant neuropathological features included spongiform degeneration, gliosis, deposition of abnormal prion protein (PrP(TSE)) and many deposits of abnormally phosphorylated tau protein (p-Tau) in several areas of the cerebrum and cerebellum. Western blots showed large amounts of proteinase K-resistant prion protein in the central nervous system. The striking absence of PrP plaques (prominent in brains of cynomolgus macaques [Macaca fascicularis] with experimentally-induced BSE and vCJD and in human patients with vCJD) reinforces the conclusion that the host plays a major role in determining the neuropathology of TSEs. Results of this study suggest that p-Tau, found in the brains of all BSE-infected monkeys, might play a role in the pathogenesis of TSEs. Whether p-Tau contributes to development of disease or appears as a secondary change late in the course of illness remains to be determined.

Fine-scale functional connectivity in somatosensory cortex revealed by high-resolution fMRI

High-resolution functional magnetic resonance imaging (fMRI) at high field (9.4 T) has been used to measure functional connectivity between subregions within the primary somatosensory (SI) cortex of the squirrel monkey brain. The hand–face region within the SI cortex of the squirrel monkey has been previously well mapped with functional imaging and electrophysiological and anatomical methods, and the orderly topographic map of the hand region is characterized by a lateral to medial representation of individual digits in four subregions of areas 3a, 3b, 1 and 2. With submillimeter resolution, we are able to detect not only the separate islands of activation corresponding to vibrotactile stimulations of single digits but also, in subsequent acquisitions, the degree of correlation between voxels within the SI cortex in the resting state. The results suggest that connectivity patterns are very similar to stimulus-driven distributions of activity and that connectivity varies on the scale of millimeters within the same primary region. Connectivity strength is not a reflection of global larger-scale changes in blood flow and is not directly dependent on distance between regions. Preliminary electrophysiological recordings agree well with the fMRI data. In human studies at 7 T, high-resolution fMRI may also be used to identify the same subregions and assess responses to sensory as well as painful stimuli, and to measure connectivity dynamically before and after such stimulations.

Distribution of neprilysin and deposit patterns of Aβ subtypes in the brains of aged squirrel monkeys (Saimiri sciureus)

Beta-amyloid (Aβ) is deposited in the parenchyma and blood vessel walls of the senescent brain, and forms lesions termed senile plaques (SPs) and cerebral amyloid angiopathy (CAA). Since in Alzheimer's disease (AD) excessive Aβ is linked to cognitive deterioration, the mechanisms of degradation and clearance of Aβ are now being researched for use in AD therapy. We conducted an immunohistochemical study of the patterns of deposition of two Aβ subtypes (Aβ40 and Aβ42) and the distribution of the Aβ degrading enzyme neprilysin (NEP) in the brains of aged squirrel monkeys, a species known to develop CAA and SPs. Aβ deposits were observed mainly in the cerebral cortex of five older monkeys, and were absent in monkeys under 12 years of age. NEP expression was observed in the caudate nucleus, putamen, globus pallidus, substantia nigra and the molecular layer of the dentate gyrus, and thus exhibited a distribution complementary to those of CAA and SPs in cerebral cortex and hippocampus. It is known that CAA is more prominent than SPs in squirrel monkey brains. However, we confirmed that Aβ40 is deposited predominantly in the arterioles of the meninges and penetrates vertically into the cerebral cortex, whereas Aβ42 is deposited predominantly in the capillaries of the cerebral cortex. These distinct patterns of deposition of Aβ subtypes are likely related to the difference in biochemical character of these two subtypes. We have demonstrated for the first time the distribution of NEP in the brain of a non-human primate, the squirrel monkey, which appears useful for research on AD treatment.