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To perform MRI in Yukatan minipigs, we took advantage of the unique organization of the Yukatan minipig brains, whose anatomy includes the cortex and the gyrus (Figure 1A) [12]. The superior, lateral and inferior views of a perfusion-fixed whole brain are shown in Figures 1B-1D. In addition, it should be noted that MRI visualizes organs with a slight geometric distortion. This is often insignificant in clinical procedures, but can be an important factor in stereotaxic procedures. To confirm stereotaxic procedures and existence of artifacts, we have done a comparative analysis with various histological sections and MR images (Figures 1E-1H). As shown in Figure 1G, the phase-encoding axis is prone to scanner-induced artifacts and phase-dependent flow artifacts were also found on all our images at the level of the large vessels of the neck. In contrast, the round contour of the column of fornix and the mammilo-thalamic tract on coronal histological sections were also round and undistorted on the acquired images with no blurring of the edges or duplication of the structures. Therefore, image artifacts in the phase-encoding direction were considered minor using the protocol proposed in our study. The anatomical landmarks similar to other mammals were identified by MRI in the Yukatan minipig brain.

T2- and T1-weighted imaging sequences provided good contrast and spatial resolution for identification of most clinically relevant brain anatomy in both the axial and sagittal planes (Figure 2). However, T2-weighted images were the most useful for identifying clinically relevant neuroanatomy. Using a slice thickness of 3.0 mm enabled reduced-volume averaging and improved spatial resolution of smaller structures (Figures 3-4). Axial plane images are shown in Figure 3. Sagittal plane images are shown in Figure 4. The striatum was fairly large, appearing as two compartments, namely the putamen and caudate nucleus. The caudate nucleus is an elongated mass of gray matter which is closely related to the lateral ventricle. The putamen is the largest part of the striatum and its most rostral portion is located lateral to the head of the caudate nucleus, separated by the anterior part of the internal capsule. The putamen is separated from cortical tissue by the external capsule (Figure 3). On sagittal T1-weighted MR images of the posterior pituitary lobe, the adenohypophysis is isointense relative to gray matter and the neurohypophysis is hyperintense (Figure 4). The globus pallidus forms the more medial part of the stratum and it is separated from the putamen by a thin layer of white matter called the lateral medullary lamina (Figures 5A-5C). The substantia nigra was identified as a broad band of gray matter dorsal to the cerebral peduncle extending from the level of the red nucleus (Figure 6A). The entire hippocampus could be visualized (Figures 6A-6C). Also, on sagittal T1-weighted MR images of the hippocampus could be visualized (Figure 6D).

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Animal models of human diseases have played a central role in biomedical research for the exploration and development of new therapies [19,20]. However, the evolutionary gap between humans and many of the applied animal models has continued to hamper direct applicability of the knowledge gained for human therapy [20,21]. Although the non-human primate model appears ideal, technical and organizational difficulties and high costs dictate the need for an alternative species. Therefore, we require animal models that reflect the geometry and complexity of the cytoarchitecture found in the human CNS as closely as possible, that are more affordable than primates. Minipigs have a relatively large brain with a human-like blood supply and immunologic response characteristics [16,20]. However, the topology of the pig hippocampus, hidden within the temporal lobe, indicates a degree of encephalization, an anatomical difference falling somewhere between that of the rodent and human brain [22]. In general, the organization of the main cortical lobes in the pig brain differs somewhat from that of humans and lacks the pronounced caudal expansion and curvature of the progressive telencephalon observed in primates [12]. Although these differences exist between pig and human brains, the pig brain, which is gyrencephalic, resembles the human brain more in anatomy, growth and development than the brains of commonly used small laboratory animals [12]. Furthermore, similarities in the gross anatomy of the pig brain to that of humans has also been demonstrated for the hippocampus, a limbic structure [23,24], as well as for subcortical and diencephalic nuclei [25,26] and brainstem structures [27,28]. Thus, the size of the pig brain permits the identification of cortical and subcortical structures by imaging techniques [12]. The CNS size and physiology and the longer lifespan of swine make them suitable for long-term evaluation of the safety and efficacy of cell therapies for CNS disorders [29,30].

While non-invasive methods for identifying the function of a particular brain region are now well established, there is still a challenge to relate location to architecture identified microscopically [31]. Here, we describe how imaging technology can now be used to identify anatomical regions based on the underlying myeloarchitecture in the living Yukantan minipig brain. Neurologic and neurodegenerative disorders and typical lesion locations as described in Table 2 are adapted from a syndrome approach to clinical neurology [32,33]. This approach attributes predictable neurodegenerative or neurologic signs to disruption of specific tracts, nuclei or nerves within one or more of the embryologic subdivisions of the brain [15,16]. As shown in Table 2, multifocal lesions or diffuse brain disease will also usually present with multiple neurologic signs, making neuroanatomic localization more complex.

Most people are familiar with MRI scans of the brain and the way they depict the internal structures of this fascinating organ [31]. The most striking feature in such scans, apart from the overall shape of the pig head, is the distinction between the convoluted surface of the brain, the cerebral cortex and the white matter connections that join different parts of the brain [31]. While MRI is useful to map the concentration of water in structures being imaged, the distinction between white matter and grey matter is resolved in a much more subtle way [16]. In the future, high-resolution MRI could become a standard method of detecting pathological changes in the brain at the earliest possible occasion, leading to early treatment and minimization of irreversible damage. In the present study, we used T1/2-weighted MRI results from six Yukatan minipigs as the basis for developing a volumetric and stereotaxic pig brain atlas. Automatic coregistration of the pig brain was obtained using 12 degrees of freedom, rather than 9 degrees typically used in human studies [34]. The relatively greater spatial uniformity of the smaller pig brain facilitates coregistration with a higher number of fitting parameters [34]; thus, the 3D surface rendering of the average pig brain preserves the major sulcal anatomy. In particular, the Sylvian fissure and the coronal fissure can clearly be seen in the average brain surface rendering. However, the fine details of sulcal and gyral anatomy were lost in the coregistration and averaging process. Furthermore, the detailed segmentation of subcortical structures is impossible to see with the present 1-T imaging. New MR data to be acquired with a 3-T magnet and with longer scanning times should improve the surface rendering of the pig brain and also reveal subcortical anatomic details. Current efforts are directed toward the registration of high-field images to histologic material sectioned in the anatomical planes defined in the common coordinate system. Although various researches on swine brain strains by MR imaging was reported, minipig brain research is concentrated in the most common or smallest miniature breeds such as Göttingen [16]. Our study provided moderate miniature breed data on macroscopic or microscopic background descriptions in the laboratory setting. Also, this work provides the basis for a planned systemic comparison of gender, age and strain differences in minipig neuroanatomy for the bio-organ research field.

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