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Shapes and Sizes of Different Mammalian Cerebella. A study in quantitative comparative neuroanatomy

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Abstract

The shape of the cerebellar cortex in fourteen mammalian species and one bird was studied by careful dissection, counts of the numbers of folia, and measurement of their length. All mammalian cerebella conformed to the same general plan, with an anterior region where folia are continuous between right and left, and three separate posterior appendages. There were, however, considerable differences between species, both in the relative length of the posterior appendages and in the relative abundance of folia on the midline compared to the lateral portions. In order to discover general laws referring to the width and length of the cerebellar cortex in their relation to body weight, cerebellar weight, and area of cerebellar cortex, an allometric analysis was performed. By plotting the values for the various species on log-log diagrams, the following statements can be inferred: 1. The weight of the cerebellar cortex is proportionate to the body weight to the power of 0.72, well comparable to the classical proportionality between brain weight and body weight to the power of 2/3 (Jerison 1973). 2. Cerebellar area and cerebellar weight are proportionate in larger animals, but in the smaller species the thickness of the cerebellar cortex varies and therefore a different dependence is valid. 3. The width of the cerebellar cortex increases with body size in the smaller species but tends to remain constant in the larger ones. 4. The longest anterior-posterior extension in our collection was measured in the bovine cerebellum. 5. The position of man in our collection of species is particular in several ways. The width of the human cerebellum is far greater than allometric relations established for the other species would suggest. Also, the vermal length of man falls short of the allometric rule established for the other species.
... formed of two large hemispheres and a rudimentary central vermis. That variation could be attributed to the structural/behavioral differences of the human in comparison to the other mammals18 . This is also in agreement with Demaerel who found that, in primates, especially the human; the large cerebellar hemispheres were because those regions received signals from the distal parts of the limbs and were commonly supposed to be involved in controlling the independent skillful movements of the fingers, hands and feet19 . ...
... We next calculated the total pial surface area of the BigBrain cerebellar cortex. The surface area was 1,945 cm 2 (Fig. 3C), which is, to the best of our knowledge, considerably larger than any reported estimate [4,[46][47][48] to date. By contrast, the BigBrain cerebral cortex area (after correction for the shrinkage) was 2864 cm 2 (= 1,848 × 1.245 2 ). ...
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The cerebellum is ontogenetically one of the first structures to develop in the central nervous system; nevertheless, it has been only recently reconsidered for its significant neurobiological, functional, and clinical relevance in humans. Thus, it has been a relatively under-studied compared to the cerebrum. Currently, non-invasive imaging modalities can barely reach the necessary resolution to unfold its entire, convoluted surface, while only histological analyses can reveal local information at the micrometer scale. Herein, we used the BigBrain dataset to generate area and point-wise thickness measurements for all layers of the cerebellar cortex and for each lobule in particular. We found that the overall surface area of the cerebellar granular layer (including Purkinje cells) was 1,732 cm ² and the molecular layer was 1,945 cm ² . The average thickness of the granular layer is 0.88 mm (± 0.83) and that of the molecular layer is 0.32 mm (± 0.08). The cerebellum (both granular and molecular layers) is thicker at the depth of the sulci and thinner at the crowns of the gyri. Globally, the granular layer is thicker in the lateral-posterior-inferior region than the medial-superior regions. The characterization of individual layers in the cerebellum achieved herein represents a stepping-stone for investigations interrelating structural and functional connectivity with cerebellar architectonics using neuroimaging, which is a matter of considerable relevance in basic and clinical neuroscience. Furthermore, these data provide templates for the construction of cerebellar topographic maps and the precise localization of structural and functional alterations in diseases affecting the cerebellum.
... In mammals, the size and morphological complexity of the cerebellum have increased considerably throughout the evolutionary process [72]. The biggest developmental difference between the chick and the mouse cerebellum is the expression of ATOH1 and NEUROD1 protein (Figure 4). ...
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Transit amplification of neural progenitors/precursors is widely used in the development of the central nervous system and for tissue homeostasis. In most cases, stem cells, which are relatively less proliferative, first differentiate into transit amplifying cells, which are more proliferative, losing their stemness. Subsequently, transit amplifying cells undergo a limited number of mitoses and differentiation to expand the progeny of differentiated cells. This step-by-step proliferation is considered an efficient system for increasing the number of differentiated cells while maintaining the stem cells. Recently, we reported that cerebellar granule cell progenitors also undergo transit amplification in mice. In this review, we summarize our and others’ recent findings and the prospective contribution of transit amplification to neural development and evolution, as well as the molecular mechanisms regulating transit amplification.
... The mean weight of the cerebellum to the brain is 16.2 % in male and 15.1 % in female mongooses, while it is 10 % in humans, 8.1 % in cows, 15.3 % in sheep, 8.3 % in dogs, 16.5 % in rabbits, 14.5 % in rats, 17.6 % in cats and 15.2 % in mice (Sultan and Braitenberg, 1993). The relatively greater size of the cerebellum is associated with the center of equilibrium. ...
... The mean weight of the cerebellum to the brain is 16.2 % in male and 15.1 % in female mongooses, while it is 10 % in humans, 8.1 % in cows, 15.3 % in sheep, 8.3 % in dogs, 16.5 % in rabbits, 14.5 % in rats, 17.6 % in cats and 15.2 % in mice (Sultan and Braitenberg, 1993). The relatively greater size of the cerebellum is associated with the center of equilibrium. ...
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Mongoose is a common name for 30 species of the family Herpestidae found in a vast area of southwestern Asia, especially Iran. Morphometric studies of the brain have been topics of interest to anatomy researchers due to their high importance in veterinary and zoology fields. The present study was conducted to better understand the brain's morphometric features in Mongoose because of the lack of information about the brain structure in wild carnivores. For this purpose, eight carcasses of adult mongooses were used. They were found in different Fars province areas in Iran, which were dead due to natural causes. The brain was then carefully separated from the skull, and all the measurements and observations related to different parts of the brain were recorded. The values entered the computer separated by gender, and SPSS 22 and T. student tests were used for statistical analysis while the significance level of P ≤ 0.05 was considered. This study showed that the ratio of brain weight to body weight (EQ) and the ratio of cerebellum weight to total brain weight in mongooses are higher than in other carnivores. All the brain's morphometric findings in mongooses are in unparalleled harmony with their lifestyle. Also, no difference was found between the mongoose and other carnivores such as dogs and cats regarding the gyri and sulci's number and pattern. The current work is a preliminary assessment, and new imaging methods are suggested for more advanced studies.
... Animals in Groups 2 through 4 underwent necropsy procedures on Days 91 (Groups 2 and 3) and 175 (Group 4). Each animal from Group 5 was chosen to be terminated Total weight of the spinal cord is assumed to be 6 g c Total brain weight is ranged from 62 to 85 g [29,30]; cerebellum weight is about 8 g [37] and cortex takes 70-80% of the brain weight d The central compartment is scaled to the total blood volume estimated based on 59.0 ± 15.0 mL/kg [31] on one of the following days: 8, 35, 42, 70, 98, or 155. At the time of sacrifice, the brain was sectioned in a brain trimming matrix at 4 mm coronal thickness. ...
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Antisense oligonucleotides (ASOs) are promising therapeutic agents for a variety of neurodegenerative and neuromuscular disorders, e.g., Alzheimer’s, Parkinson’s and Huntington’s diseases, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), caused by genetic abnormalities or increased protein accumulation. The blood–brain barrier (BBB) represents a challenge to the delivery of systemically administered ASOs to the relevant sites of action within the central nervous system (CNS). Intrathecal (IT) delivery, in which drugs are administered directly into the cerebrospinal fluid (CSF) space, enables to bypass the BBB. Several IT-administered ASO therapeutics have already demonstrated clinical effect, e.g., nusinersen (SMA) and tofersen (ALS). Due to novelty of IT dosing for ASOs, very limited pharmacokinetic (PK) data is available and only a few modeling reports have been generated. The objective of this work is to advance fundamental understanding of whole-body distribution of IT-administered ASOs. We propose a physiologically-based pharmacokinetic modeling approach to describe the distribution along the neuroaxis based on PK data from non-human primate (NHP) studies. We aim to understand the key processes that drive and limit ASO access to the CNS target tissues. To elucidate the trade-off between parameter identifiability and physiological plausibility of the model, several alternative model structures were chosen and fitted to the NHP data. The model analysis of the NHP data led to important qualitative conclusions that can inform projection to human. In particular, the model predicts that the maximum total exposure in the CNS tissues, including the spinal cord and brain, is achieved within two days after the IT injection, and the maximum amount absorbed by the CNS tissues is about 4% of the administered IT dose. This amount greatly exceeds the CNS exposures delivered by systemic administration of ASOs. Clearance from the CNS is controlled by the rate of transfer from the CNS tissues back to CSF, whereas ASO degradation in tissues is very slow and can be neglected. The model also describes local differences in ASO concentration emerging along the spinal CSF canal. These local concentrations need to be taken into account when scaling the NHP model to human: due to the lengthier human spinal column, inhomogeneity along the spinal CSF may cause even higher gradients and delays potentially limiting ASO access to target CNS tissues.
... When analyzing the distribution of the thickness of the molecular and granular layers in the different subjects comprising our study population, it appears that the measurements are quite consistent and regular, in contrast with what Sultan and Braitenberg (1993) had reported for smaller mammalian species. ...
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Guinea pigs have proved useful as experimental animal models in studying cerebellar anatomical and structural alterations in human neurological disease; however, they are also currently acquiring increasing veterinary interest as companion animals. The morphometric features of the normal cerebellum in guinea pigs have not been previously investigated using stereology. The objective of the present work was to establish normal volumetric and quantitative stereological parameters for cerebellar tissues in guinea pigs, by means of unbiased design‐based stereology. Cerebellar total volume, gray and white matter volume fractions, molecular and granular layers volume fractions, cerebellar surface area, Purkinje cellular and nuclear volumes, and the Purkinje cell total count were stereologically estimated. For this purpose, cerebellar hemispheres from six adult male guinea pigs were employed. Isotropic, uniform random sections were obtained by applying the orientator method, and subsequently processed for light microscopy. The cerebellar total volume, the white and grey matter volume fractions, and the molecular and granular layer volumes were estimated using the Cavalieri's principle and the point counting system. The cerebellar surface area was estimated through the use of test lines; Purkinje cellular and nuclear volumes were analysed using the nucleator technique, whereas the Purkinje cell total count was obtained by means of the optical disector technique. The mean ± standard deviation total volume of a guinea‐pig cerebellar hemisphere was 0.11 ± 0.01 cm3. The mean volumetric proportions occupied by the gray and white matters were, respectively, 78.0 ± 2.6% and 22.0 ± 2.6%, whereas their mean absolute volumes were found to be 0.21 ± 0.02 cm3 and 0.059 ± 0.006 cm3. The volumes of the molecular and granular layers were estimated at 112.4 ± 20.6 mm3 and 104.4 ± 7.3 mm3, whereas their mean thicknesses were calculated to be 0.184 ± 0.020 mm and 0.17 ± 0.02 mm. The molecular and granular layers accounted for 40.7 ± 3.9% and 37.4 ± 1.8% of total cerebellar volume respectively. The surface area of the cerebellum measured 611.4 ± 96.8 mm2. Purkinje cells with a cellular volume of 3210.1 µm3 and with a nuclear volume of 470.9 µm3 had a higher incidence of occurrence. The mean total number of Purkinje cells for a cerebellar hemisphere was calculated to be 253,090 ± 34,754. The morphometric data emerging from the present study provide a set of reference data which might prove valuable as basic anatomical contribution for practical applications in veterinary neurology.
... This is considerably larger than any previous estimate. For comparison, the largest previous estimate was 1,128 cm 2 reported by Sultan and Braitenberg (12). Previous MRI-based estimates from in vivo MRI scans were uniformly much smaller because individual folia were not completely resolved, as noted by the authors [e.g., Van Essen (13), 540 cm 2 ; cerebellar high-resolution map (CHROMA) atlas external surface, 390 cm 2 ; Diedrichsen and Zotow (16): gray/white matter surface, 125 cm 2 ]. ...
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Significance The cerebellum has long been recognized as a partner of the cerebral cortex, and both have expanded greatly in human evolution. The thin cerebellar cortex is even more tightly folded than the cerebral cortex. By scanning a human cerebellum specimen at ultra-high magnetic fields, we were able to computationally reconstruct its surface down to the level of the smallest folds, revealing that the cerebellar cortex has almost 80% of the surface area of the cerebral cortex. By performing the same procedure on a monkey brain, we found that the surface area of the human cerebellum has expanded even more than that of the human cerebral cortex, suggesting a role in characteristically human behaviors, such as toolmaking and language.
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Distinct regions of the cerebellum connect to separate regions of the cerebral cortex forming a complex topography. While cerebellar organization has been examined in group-averaged data, study of individuals provides an opportunity to discover features that emerge at a higher spatial resolution. Here functional connectivity MRI was used to examine the cerebellum of two intensively-sampled individuals (each scanned 31 times). Connectivity to somatomotor cortex showed the expected crossed laterality and topography of the body maps. A surprising discovery was connectivity to the primary visual cortex along the vermis with evidence for representation of the central field. Within the hemispheres, each individual displayed a hierarchical progression from the inverted anterior lobe somatomotor map through to higher-order association zones. The hierarchy ended at Crus I/II and then progressed in reverse order through to the upright somatomotor map in the posterior lobe. Evidence for a third set of networks was found in the most posterior extent of the cerebellum. Detailed analysis of the higher-order association networks revealed robust representations of two distinct networks linked to the default network, multiple networks linked to cognitive control, as well as a separate representation of a language network. While idiosyncratic spatial details emerged between subjects, each network could be detected in both individuals, and seed regions placed within the cerebellum recapitulated the full extent of the spatially-specific cerebral networks. The observation of multiple networks in juxtaposed regions at the Crus I/II apex confirms the importance of this zone to higher-order cognitive function and reveals new organizational details.
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Background and Objectives: Surgical simulators are widely used to promote faster and safer surgical training. They not only provide a platform for enhancing surgical skills but also minimize risks to the patient’s safety, operation theatre usage, and financial expenditure. Retracting the soft brain tissue is an unavoidable procedure during any surgery to access the lesioned tissue deep within the brain. Excessive retraction often results in damaging the brain tissue, thus requiring advanced skills and prior training using virtual platforms. Such surgical simulation platforms require an anatomically correct computational model that can accurately predict the brain deformation in real-time. Methods: In this study, we present a 3D finite element brain model reconstructed from MRI dataset. The model incorporates precisely the anatomy and geometrical features of the canine brain. The brain model has been used to formulate and solve a quasi-static boundary value problem for brain deformation during brain retraction. The visco-hyperelastic framework within the theory of non-linear elasticity has been used to set up the boundary value problem. Consequently, the derived non-linear field equations have been solved using finite element solver ABAQUS. Results: The retraction simulations have been performed for two scenarios: retraction pressure in the brain and forces required to perform the surgery. The brain was retracted by 5 mm and retained at that position for 30 minutes, during which the retraction pressure attenuates to 36% of its peak value. Both the model predictions as well as experimental observations on canine brain indicate that brain retraction up to 30 minutes did not cause any significant risk of induced damage. Also, the peak retraction pressure level indicates that intermittent retraction is a safer procedure as compared to the continuous retraction, for the same extent of retraction. Conclusions: The results of the present study indicate the potential of a visco-hyperelastic framework for simulating deep brain retraction effectively. The simulations were able to capture the dominant characteristics of brain tissue undergoing retraction. The developed platform could serve as a basis for the development of a detailed model in the future that can eventually be used for effective preoperative planning and training purposes.
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