rubrospinal projection, if a substantial number of rubrospinal neurons were small [45]. Papez and Stottler (1940) showed that in human infants, small cells located caudal and lateral in the red nucleus project to the contralateral spinal cord [46]. Using tissue from an adult patient with an old paramedian infarct involving the red nuclei, Terao and co-workers (1996) reported that small myelinated fibers in the lateral corticospinal tract were selectively diminished at all spinal cord levels compared with large myelinated fibers. They suggested that some of these diminished small myelinated fibers may correspond to the human rubrospinal tract [47]. The human red nucleus was previously considered to correspond to the rubral complex of nuclei. In quadrupeds, this complex consists of the mNr and the mesodiencephalic nuclei projecting to the inferior olive via both the CTT and MTT (for rat, see Ruigrok and Cella, 1995 [23]; for cat, see Ogawa, 1939 [1]). However the present study shows clearly that the CTT components (i.e., NB-pNr complex) and the rudimentary semi- lunar shell of mNr actually correspond to the human red nucleus. Evolutionary Consideration Although it is believed generally that the primate mNr shows a consistent trend toward gradual functional and anatomical diminution during the progress of evolution, as a matter of fact this is not the case. Those primates that are proficient at terrestrial quadrupedalism exhibit a very well-developed mNr. Examples are the macaque and baboon [42,43]. Both corticorubral and corticospinal neurons mix well in the motor cortex of such monkeys. However, the mNr of apes (e.g., gibbon and chimpan- zee) shows a consistent trend to decrease gradually along the phylogenetic scale [48,49,43,50]. Correspondingly, the corticoru- bral neurons of these apes may have followed a gradual decrease. This reduction of the role of the mNr is considered to be a consequence of a dynamic continuous change in cerebral organization that is furthered by neuronal competition. The chimpanzee’s mNr is the smallest and most limited in size for quadrupedalism and arboreal life. Anatomical data (Sobel 1977 [44]) have shown that the cell count in the chimpanzee’s mNr (ca. 1,250) is 2.8 times greater than that in humans (ca. 450 cells). Neurons of the human mNr are found in a variety of sizes: giant, large, medium and small cells [44]. Humans are known to possess 150–200 giant-to-large sized neurons in that portion of the mNr which project large myelinated fibers not only to the brain stem but also within the first three cervical segments (Nathan & Smith 1982 [39]). Therefore there must remain the possibility that there were these mNr neurons related to limb control associated with propriospinal neurons in upper cervical segments, and that these projected extensively throughout the cervical enlargement (Nathan et al. 1996 [51]), being related to shoulder movement [37]. Our previous studies [3,33,28,52,24] have shown that the mesodiencephalic nuclei, including the ND, NB and pNr, show developmental differences corresponding to species-specialized body parts, such as the human hand, the elephant’s trunk and the whale’s axial musculature system. Onodera and Hicks (1999) [52] proposed that the phylogenetically newer pyramidal tract and well-developed mesodiencephalo-olivo-cerebellar circuits ‘‘broke through’’ the constraints of the older rubrospinal system of the mNr and suggested that the human pyramidal system took over to provide a tonically active framework for locomotor function, rather than actually physically replacing the rubrospinal system. The transient prominence of the fetal and infant mNr discussed above might have provided the organism with a functional rubrospinal projection. This may have permitted the transition from the rubrospinal system to corticospinal system: i.e., subsequent New Model of Human Red Nucleus Figure 15. Human cerebro-cerebellar system. The medial cerebellar system receives cortical information from areas 4, 8 and 7 via the ND [62,63,38,56]. The lateral cerebellar system might not have been related only to skilful motor learning via areas 4, 6, 5 and 8 [35,36,63,38,56], but also to cognitive and language processing via the prefrontal cortico-rubral projection. CTT–central tegmental tract, dD– dorsal half of cerebellar dentate nucleus, dl–dorsal lamella, Gl– cerebellar globose nucleus, lb–lateral bend, MAO–medial accessory olive, MTT–medial tegmental tract, NB–nucleus accessorius medialis of Bechterew, ND–nucleus of Darkschewitsch, pNr–parvicellular red nucleus, PO–principal olive, vD–ventral half of cerebellar dentate nucleus, vl–ventral lamella, 4–motor area, 5–somatosensory association cortex, 6–premotor area, 7–posterior parietal cortex, 8–frontal eye field, 44–Broca’s speech area. doi:10.1371/journal.pone.0006623.g015 normal development of the corticospinal system during ontogeny. It is known from current observation of human infants that once certain key milestones are achieved for stabilization of each body segment (the head, upper and lower torso segments and crawling behavior), standing is achieved, balancing behavior performed, as is low-velocity, bipedal locomotion that typically begins around one year of age. The acquisition of bipedalism demands not only the maturation of the body’s phenotype but also the reorganization of the nervous system. Clearly evolution cannot occur by transforma- tion from one adult form to another adult form, but by ontogenetic change over time. Humans have taken several million years to establish bipedalism through changes of the genetic pool, while individual humans after birth take several years to establish the same process, of course without any genetic change. Using voxel-based morphometric analyses, Vargha-Khaden and her coworkers (2005) showed that the affected KE family members with a higher-order orofacial motor impairment during speech have significantly reduced grey matter in the inferior frontal gyrus (Broca’s area), the precentral gyrus, the temporal pole, the head of the caudate nucleus and the ventral cerebellum (lobules VIIB and VIIIB) [53]. In the normal human fetus, the FOXP2 gene is expressed in not only the cerebral cortex, basal ganglia and thalamus, but also the cerebellum, inferior olivary complex and red nucleus (Lai et al., 2003 [54]; Teramitsu et al., 2004 [55]). These data propose that one circuit for FOXP2-dependent speech and language might be not only the prefronto-caudate-loop but also the inferior fronto (Broca’s area)- rubro-olivo-lateral cerebellar loop. The NB may receive projections from ventral area 6, within and caudal to the inferior ramus of the arcuate sulcus (see Leichnetz et PLoS ONE | www.plosone.org 17 August 2009 | Volume 4 | Issue 8 | e6623