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To safeguard patients, regulatory authorities require that new drugs that are to be given by the intravitreal (IVT) route are assessed for their safety in a laboratory species using the same route of administration. Due to the high similarity of ocular morphology and physiology between humans and nonhuman primates (NHPs) and due to the species spec...
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Context 1
... of many biotherapeutics, the monkey often is the only appropriate species for preclinical safety testing. To this end, intravitreal administration procedures and assessments of ocular toxicity in cynomolgus monkeys (Macaca fascicularis) are well established ( Niggemann et al., 2006). In contrast, the common marmoset monkey (Callithrix jacchus; Fig. 1) is not a standard model for ocular toxicity studies due to its general sensitivity to laboratory investigations and small eye ...
Context 2
... the implicit times decrease with increasing stimulus strength. The absolute values of the scotopic a-and b-wave amplitudes measured with 3 cd·s m −2 flashes agree with those measured in humans at the same conditions (Hamilton et al., 2015). The implicit time of the a-wave at the same flash strength was also similar to those measured in human subjects. ...
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Citations
... For example, species with large eyes relative to the brain size (e.g., marmosets) tend to have a large or positive pitch (frontal downward direction) of the stereotactic coordinate relative to AC-PC plane, whereas species (e.g., human and macaque) with relatively smaller eyes tend to have a smaller or negative pitch (frontal upward direction). Indeed, the volume ratio of eyeball to brain is substantially larger in marmoset (10%) (Korbmacher et al., 2017) in comparison to macaque monkeys (3%) (Atsumi et al., 2013) and humans (0.4%) (Heymsfield et al., 2016). ...
Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses.
Highlights
Achieved sub-millimeter localization accuracy of subject-wise brain region
Propose a dedicated non-invasive multi-modal subject-specific registration pipeline
Construct brain coordinate system in AC-PC and grayordinate spaces
Establish multi-modal MRI and CT brain and cortical templates, MarmosetRIKEN20
Quantify intersubject variabilities in marmoset brain
Significant bias and uncertainty exist in marmoset stereotactic positioning
Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.
Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses.
