Fetal Gyrification in Cynomolgus Monkeys: A ... - Wiley Online Library

THE ANATOMICAL RECORD 295:1065–1074 (2012)

Fetal Gyrification in Cynomolgus Monkeys: A Concept of Developmental Stages of Gyrification KAZUHIKO SAWADA,1* KATSUHIRO FUKUNISHI,2 MASATOSHI KASHIMA,2 SHIGEYOSHI SAITO,3,4 HIROMI SAKATA-HAGA,5 ICHIO AOKI,3 5 AND YOSHIHIRO FUKUI 1 Laboratory of Anatomy, Department of Physical Therapy, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Ibaraki, Japan 2 Shin Nippon Biomedical Laboratories, Kagoshima, Japan 3 Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan 4 Department of Medical Engineering, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan 5 Department of Anatomy and Developmental Neurobiology, University of Tokushima Graduate School Institute of Health Biosciences, Tokushima, Japan

ABSTRACT Our article summarizes a series of studies about fetal gyrification and its relation to cerebral growth in cynomolgus monkeys. Based on the cerebral growth (i.e., brain weight, cerebral volume, and frontooccipital length of the cerebral hemisphere) and the developmental pattern of gyrification in each sulcus of cynomolgus monkeys, we divided the gyrification process into four stages: Stage 1. Demarcation of cerebral lobes and limbic gyri; Stage 2. Demarcation of neocortical gyri; Stage 3. Emergence of secondary and tertiary sulci; and Stage 4. Growth of sulcal length and depth. Each stage of those gyrification processes was influenced by different developmental events, such as the emergence of corticocortical long-associative fiber tracts, cortical maturations, and subcortical white-matter development. This is the first report to systematically propose gyrification processes closely related to the order of phyologenetical development of the cerebral cortex in primates. C 2012 Wiley Periodicals, Inc. Anat Rec, 295:1065–1074, 2012. V

Key words: macaque; MRI; sulcation; gyration; phylogeny

INTRODUCTION In primate species, the cerebral cortex changes from a lissencephalic to a gyrencephalic structure in the course of its maturation (Chi et al., 1977; Garel et al., 2001; Fukunishi et al., 2006; Kashima et al., 2008; Sawada et al., 2009; Sawada et al., 2012). The cerebral sulci and gyri provide a natural topographic partition that corresponds to their cytoarchitectural, myeloarchitectural and/or thalamocortical borders (Maudgil et al., 1998). As in humans, functional MRI studies have shown the topological relationships of the primary sulci and gyri with functional cortical divisions such as eye fields, auditory areas, primary motor areas, and orbital fields in monkeys (Chiavaras and Petrides, 2000; Koyama et al., 2004; Grefkes and Fink, 2005). The degree of cortical convolution (gyrification) has varied among mammalian species (Zilles et al., 1988, C 2012 WILEY PERIODICALS, INC. V

1989; Wosinski et al., 1996; Pillay et al., 2007), and a rostrocaudal pattern of gyrification through the cerebral hemisphere has indicated a species-specific pattern formation of cortical organization (Zilles et al., 1988, 1989). While the mean degree of gyrification in the entire cerebrum is increased in higher orders of primates (Zilles et al., 1988, 1989; Pillay et al., 2007), the rostrocaudal Grant sponsor: JSPS KAKENHI; Grant number: 20590176. *Correspondence to: Kazuhiko Sawada, Laboratory of Anatomy, Department of Physical Therapy, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Ibaraki 300-0051, Japan. Fax: þ81-29-826-6776. E-mail: [email protected] Received 9 January 2012; Accepted 19 March 2012. DOI 10.1002/ar.22478 Published online 17 May 2012 in Wiley Online Library (wileyonlinelibrary.com).

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pattern of gyrification has varied among primate species, that is, gyrification is low throughout the cerebral cortex in prosimians, increasing significantly over the posterior region in catarrhines, and uniformly greater in humans (Zilles et al., 1988). Developmentally, gyrification progresses first at the level of the central region, second in the temporo-parieto-occipital lobe, and third in the frontal lobe in humans (Dubois et al., 2008) and cynomolgus monkeys (Sawada et al., 2010). Thus, the developmental pattern of gyrification is phylogenetically homologous among primate species, and the interspecies difference in the gyrification pattern arises from the progression of cortical infolding in the frontal region following an infolding of the temporo-parieto-occipital region. Several studies have addressed the possible mechanisms of gyrification, for example, genetic control (Rakic et al., 2004), differential growth of inner and outer cortical strata (Caviness, 1975), cortical growth (Toro and Burnod, 2005), and tension from white matter axons (Caviness, 1975; Evrard et al., 1978; Armstrong et al., 1991; Van Essen, 1997). No integrated understanding of the many aspects of gyrification has proved sufficient to date. This article summarizes our series of studies on fetal gyrification and its relation to cerebral growth in cynomolgus monkeys during the later half of gestation (the gestation period of this primate is 140–150 days). We propose a new concept of the developmental stages of gyrification in primates based on cerebral growth and patterns of gyrification. All of our previous studies referred to in this article were approved by the Institutional Animal Care and Use Committee of Shin Nippon Biomedical Laboratories, and were conducted in accordance with the Principles of Laboratory Animal Care (No. 86-23, 1985 revision of the National Institutes of Health (NIH)), and with the ethics criteria stated in the bylaws of the Experimental Animal Ethics Committee of Shin Nippon Biomedical Laboratories.

embryonic days (EDs) 70–150 (Fig. 1), together with a timetable for the fetal sulcation in this primate, which was produced from a combination of gross anatomical and MRI results (Table 1). The primary sulci in cynomolgus monkeys emerged in a regular sequence as follows: The fetal sulcation began to emerge in the lateral fissure (lf) and in the callosal sulcus (cas) and hippocampal sulcus (his) on ED 70. It subsequently emerged in the parietooccipital sulcus (pos), calcarine sulcus (cal) and olfactory sulcus (olfs) on ED 80; the central sulcus (cs), superior temporal sulcus (sts), preoccipital notch (pon), inferior occipital sulcus (ios), arcuate sulcus (ars) and circular sulcus (cir) on ED 90; the cingulate sulcus (cgs), rhinal fissure (rf), lunate sulcus (lu), external calcarine sulcus (ecal), intraparietal sulcus (ips) and medial orbital sulcus (morb) on ED 100; the superior calcarine sulcus (scal), inferior calcarine sulcus (ical) and principle sulcus (ps) on ED 110; the occipitotemporal sulcus (ots), anterior middle temporal sulcus (amt), intermediate temporal sulcus (imt), collateral sulcus (cos), superior middle postcentral dimple (su), lateral orbital sulcus (lorb) on ED 120; and the posterior middle temporal sulcus (pmt), intermediate orbital sulcus (iorb) and rostral sulcus (ros) on ED 130 (Table 1). When compared with the emergence of anatomically identical primary sulci defined by gross observation between cynomolgus monkeys and humans, the chronology was homologous except for the earlier emergence of the cingulate (cgs) and collateral (cos) sulci in cynomolgus monkeys than in humans (Table 2). Those sulci are known to be located partly in the phylogenetically newer cortical regions used for cognition, recognition and/or language in humans (Ungerleider et al., 1998; Allman et al., 2002; Bokde et al., 2006; Carmody and Lewis, 2006). Therefore, a delay in the emergence of these sulci may be influenced by a phylogenetical specification of the cortical regions in humans.

FETAL SULCATION IN CYNOMOLGUS MONKEYS

FETAL GYRATION IN CYNOMOLGUS MONKEYS

The chronology of fetal sulcation in cynomolgus monkeys using gross anatomical observations (Fukunishi et al., 2006; Kashima et al., 2008) and ex vivo MRI with a high spatial resolution at 7-T (Sawada et al., 2009) was reported previously. In these studies, the timetable of fetal sulcation by gross observation and MRI corresponded with a lag time of 10–30 days. Such a difference in the detectability of some sulci between two techniques seemed to be associated with the length, depth, width, and location of the sulci. MRI could more readily detect them when the sulci emerged as large shallow indentations. For example, the superior temporal sulcus (sts), collateral sulcus (cos), inferior occipital sulcus (ios), arcuate sulcus (ars), inferior orbital sulcus (iorb), lateral orbital sulcus (lorb), and hippocampal sulcus (his) were visible 10–30 days earlier by MRI than by gross observation (Sawada et al., 2009). In contrast, the emergence periods of small sulci and dimples were determined later by MRI than by gross observation. For example, the olfactory sulcus (olf) and rhinal fissure (rf) were distinguishable on MR slices 10–20 days later than by gross observations, respectively (Sawada et al., 2009). Here, we present gross anatomical images of the lateral and medial cerebral surfaces of cynomolgus monkeys on

Based on fetal sulcation defined by the gross observation, we further summarized the chronological order of the demarcations of cerebral lobes and gyri in cynomolgus monkeys (Table 3). The timetables for the gyral emergence in cynomolgus monkeys and for fetal sulcation were homologous to those in humans. An exception was the gyri in the parietooccipital region such as the cuneus, angular gyrus, and supramarginal gyrus, which developed earlier in cynomolgus monkeys than in humans. These three gyri are topologically associated with the dorsal extrastriate cortex in monkeys but with the Wernicke’s area in humans, because the phylogenetically older dorsal extrastriate cortex shifts superiorly away from the posterior perisylvian region in humans, enabling the emergence of phylogenetically newer areas for language (Ungerleider et al., 1998). Such phylogenetical specification in the human cerebrum may delay the gyral convolution of this region.

PROPOSED DEVELOPMENTAL STAGES OF GYRIFICATION PROCESSES On the basis of fetal sulcation and gyration patterns, we divided the gyrification process into three stages.

FETAL GYRIFICATION IN CYNOMOLGUS MONKEYS

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Fig. 1. Photographs of lateral and medial views of cerebral surfaces and their schematic drawings, which indicate cerebral sulci in cynomolgus monkeys on embryonic days (EDs) 70–150. Bar ¼ 1 cm [adapted from Fukunishi et al. (2006); Kashima et al. (2008) and Sawada et al. (2009, 2010)].

Furthermore, a fourth stage was added (see ‘‘Degree of gyrification’’ section in detail).

Stage 1: Demarcation of Cerebral Lobes and Limbic Cortical Gyri (EDs 70-100) The primary sulci demarcating four cerebral lobes emerge at this stage, that is, the lateral fissure (ED 70), parietooccipital sulcus (ED 80), central sulcus (ED 90), and preoccipital notch (ED 90) (Table 1). In addition, gyri in the limbic cortex were also demarcated at this stage, that is, the cingulate gyrus, precuneus and parahippocampal gyrus on ED100 (Table 3). In humans, Stage 1 may be identical to the 14–23 weeks of gestation, because the cerebral lobes and limbic cortical gyri are demarcated during those gestational periods (Chi et al., 1977).

Stage 2: Demarcation of Neocortical Gyri (EDs 100-120) Almost all primary sulci that demarcated the neocortical cerebral gyri appeared between EDs 100 and 120, except that the time of emergence was earlier in the superior temporal and calcarine sulci (ED 80) and later in the posterior middle temporal, intermediate orbital and rostral sulci (ED 130) (Table 1). Accompanied by the emergence of the primary sulci, almost all neocortical gyri emerged between EDs 100 and 120, that is, the pre-

central gyrus, supramarginal gyrus and angular gyrus on ED 100; the cuneus on ED 110; the inferior and middle temporal gyri, postocentral gyrus, superior parietal lobule, superior, middle and inferior frontal gyri, inferior occipital gyrus, lingual gyrus and fusiform gyrus on ED 120 (Table 3). An exception was the superior temporal gyrus, which emerged on ED 80 because the sulci demarcating this gyrus (the lateral fissure and superior temporal sulcus) appeared at an earlier stage. In humans, Stage 2 may be identical to the 24–31 weeks of gestation, because the gyri in the neocortex also emerged during these gestational periods, whereas the superior temporal gyrus appeared at an earlier stage (20–23 weeks of gestation) (Chi et al., 1977).

Stage 3: Emergence of Secondary and Tertiary Sulci (EDs 120-150) Small sulci and dimples emerged during EDs 120–150 in cynomolgus monkeys, that is, the anterior subcentral dimple (asd), anterior parietooccipital sulcus (apos) and subparietal sulcus (sbps) on ED 120; the superior precentral dimple (spcd) and posterior supraprinciple dimple (pspd) on ED 130; and the anterior supraprinciple dimple (aspd) on ED 150 (Table 1). These sulci and dimples are recognized as secondary and tertiary sulci, because they are not related to demarcations of either the cerebral lobes or gyri. In humans, Stage 3 may be identical to the gestational period between 32 weeks and birth, because

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TABLE 1. Chronologies of emergence of cerebral sulci of cynomolgus monkey fetuses by neuroanatomic findings and ex vivo MRI

Major cerebral sulci Lateral fissure (lf) Central sulcus (cs) Parietooccipital sulcus (pos) Preoccipital notch (pon) Calcarine sulcus (cal) Cingulate sulcus (cgs) Callosal sulcus (cas) Temporal lobe Superior temporal sulcus (sts) Occipitotemporal sulcus (ots) Anterior middle temporal sulcus (amt) Intermediate middle temporal sulcus (imt) Posterior middle temporal sulcus (pmt) Rhinal fissure (rf) Collateral sulcus (cos) Occipital lobe Lunate sulcus (lu) Inferior occipital sulcus (ios) External calcarine sulcus (ecal) Superior calcarine sulcus (scal) Inferior calcarine sulcus (ical) Parietal lobe Intraparietal sulcus (ips) Superior postcentral dimple (su) Posterior subcentral sulcus (pscs) Frontal lobe Arcuate sulcus (ars) Principle sulcus (ps) Medial orbital sulcus (morb) Intermediate orbital sulcus (iorb) Lateral orbital sulcus (lorb) Superior precentral dimple (spcd) Anterior subcentral dimple (asd) Infraprinciple dimple (ipd) Posterior supraprinciple dimple (pspd) Anterior supraprinciple dimple (aspd) Olfactory sulcus (olfs) Rostral sulcus (ros) Insula Circular sulcus (cirs) Limbic cortex Hippocampal sulcus (his) Anterior parietoccipital sulcus (apos) Subparietal sulcus (sbps)

Gross observation

MRI

ED 70 ED 90 ED 80 ED 90 ED 80 ED 100 ND

ED 70 ED 90 ED 80 ED 100 ED 80 ED 100 ED 70

ED 90 ED 120 ED 120

ED 80 ED 120 ED 120

ED 120

ED 130

ED 130

ED 130

ED 100 ED 130

ED 120 ED 120

ED ED ED ED ED

100 100 100 110 110

ED 100 ED 90 ED 110 ED 110 ED 110

ED 100 ED 120 ED 130

ED 100 ED 120 ED 140

ED ED ED ED ED ED ED ED ED

100 110 120 140 140 130 130 140 140

ED 90 ED 110 ED 100 ED 130 ED 120 ED 140 ED 120 ED 150 ED 130

ED 150

ED 150

ED 80 ED 150

ED 90 ED 130

ND

ED 90

ED 100 ED 130

ED 70 ED 120

ED 140

ED 120

ND, not determined. This table was reproduced from our previous study (Sawada et al., 2009).

the secondary and tertiary sulci emerge 32 weeks after the gestational week, when the emergence of the primary sulci is complete (Chi et al., 1977).

Stage 4: Growth of Sulcal Length and Depth After Birth The increased gyrification during postnatal periods may reflect changes in the sulcal length and depth in

relation to cortical maturations (See ‘‘Degree of gyrification’’ section in detail).

BRAIN WEIGHT, FRONTO-OCCIPITAL LENGTH OF CEREBRAL HEMISPHERE AND CEREBRAL VOLUMES Our previous study measured the brain weight, fronto-occipital length (FO-length) of the cerebral hemisphere, and volumes of the entire cerebrum and cerebral cortex (Fukunishi et al., 2006; Kashima et al., 2008; Sawada et al., 2010), using the same specimens of formalin-fixed cerebra from EDs 70 to 150 of fetuses that had been sampled in our study (Fukunishi et al., 2006). The brain weight increased in the shape of a sigmoidal curve (triphasic curve) from EDs 70 to 150, a slow increase between EDs 70 and 90, a rapid increase between EDs 90 and 130, and again, a slow increase after ED 140 (Fig. 2A). Interestingly, a gain in the mean value of the brain weight showed two peaks, that is, markedly higher levels on EDs 100 and ED 120 than on embryonic ages (Fig. 2B). Along the FO length, the entire cerebral and cerebral cortical volumes also began to increase drastically from ED 100 (Fig. 2C,D), corresponding to the first peak of the brain weight gain. As described in the Section on ‘‘Fetal sulcation in cynomolgus monkeys,’’ almost all the neocortical gyri in cynomolgus monkeys were demarcated at Stage 2 of the gyrification process (between EDs 100 and 120). Therefore, increases in the brain weight and cerebral volume at Stage 2 may be involved in gyral formations in the neocortex, while the increases at Stages 3 and 4 may be involved in the generation of secondary and tertiary sulci and/or the progression of sulcal infolding.

DEGREE OF GYRIFICATION The degree of gyrification is usually evaluated by either the gyrification index (GI) (Zilles et al., 1988, 1989) or the sulcation index (SI) (Dubois et al., 2008). The GI is based on the ratio of the superficial contour to the outer contour of coronal slices of the cerebrum (Zilles et al., 1988, 1989; Armstrong et al., 1995), and is considered a suitable quantitative method for comparing either between species or within a single species at various stages of cortical development. The GI is thought to be essential for an enhanced understanding of the pathogenesis of the primate cerebrum, because the GI was altered in developmental and psychological disorders such as schizophrenia and autism (Kulynych et al., 1997; Vogeley et al., 2000, 2001; Levitt et al., 2003; Sallet et al., 2003; Harden et al., 2004; Harris et al., 2004a,b; Jou et al., 2005; Kippenhan et al., 2005; Nierenberg et al., 2005; Rapoport et al., 2005; Bonnici et al., 2007). We estimated the GI of the cerebrum of cynomolgus monkeys from EDs 70 to 150, using a series of coronal MR slices obtained from the formalin-fixed cerebra that we used in our gross anatomical observations of sulcation and gyration (Fukunishi et al., 2006; Kashima et al., 2008) as well as in our measurements of brain weight, FO-length, and volumes of the entire cerebrum and cerebral cortex (Fukunishi et al., 2006; Kashima et al., 2008; Sawada et al., 2010) described in the Section on Fetal gyration in cynomolgus monkeys.

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TABLE 2. Comparison of chronologies of primary sulcal emergence between cynomolgus monkeys and humans Humana

Cynomolgus monkey ED 70 ED 80

ED 90 ED 100 ED 120

Lateral fissure (lf) Parietooccipital sulcus (pos) Olfactory sulcus (olf) Calcarine sulcus (cal) Superior temporal sulcus (sts) Central sulcus (cs) Cingulate sulcus (cgs) Intraparietal sulcus (ips) Anterior middle temporal sulcus (amt) Occipitotemporal sulcus (ots) Collateral sulcus (cos)

GW 14 GW 16 GW 18

Lateral fissure Parietooccipital sulcus Olfactory sulcus Calcarine sulcus Cingulate sulcus

GW 20 GW 23

Central sulcus Superior temporal sulcus Collateral sulcus

GW 26

Intraparietal sulcus Inferior temporal sulcus Occipitotemporal sulcus

GW 30

Cerebral sulci on same lines are anatomically identical between humans and cynomolgus monkeys. According to Chi et al. (1977). This table was reproduced from our previous study (Kashima et al., 2008).

a

TABLE 3. Comparison of chronologies of demarcation of cerebral gyri between cynomolgus monkeys and humans Humana

Cynomolgus monkey ED 80 ED 100

ED 110 ED 120

Superior temporal gyrus Parahippocampal gyrus Precentral gyrus Supramarginal gyrus Angular gyru Cingulate gyrus Cuneus Postcentral gyrus Superior frontal gyrus Superior parietal lobule Middle temporal gyrus Middle frontal gyrus Inferior temporal gyrus Inferior occipital gyrus Lingual gyrus Fusiform gyrus

GW 18 GW 23 GW 24

GW 25 GW 26 GW 27

GW 28 GW 30

Cingulate gyrus Superior temporal gyrus Parahippocampal gyrus Precentral gyrus

Postcentral gyrus Superior frontal gyrus Superior parietal lobule Middle temporal gyrus Middle frontal gyrus Inferior occipital gyrus Lingual gyrus Fusiform gyrus Cuneus Supramarginal gyrus Angular gyrus Inferior temporal gyrus

Cerebral gyri on same lines are anatomically identical between humans and cynomolgus monkeys. a According to Chi et al. (1977). This table was reproduced from our previous study (Kashima et al., 2008).

The mean GI of the cerebrum of cynomolgus monkeys remained low (1.1–1.2) during EDs 70–90, then increased drastically on ED 100 and thereafter, while failing to reach a plateau by ED 150 (Fig. 2E). The earlier slowly increasing phase of the GI during EDs 70–90 corresponded to Stage 1 of the gyrification processes, while the subsequent increasing phase during EDs 100– 150 corresponded to Stages 2 and 3. In humans, the mean GI increases drastically from GW 24 (Armstrong et al., 1995), corresponding to the onset of Stage 2 of the gyrification process. Furthermore, the mean GI values correlated closely with the entire cerebral volume in cynomolgus monkeys (r ¼ 0.9797) (Fig. 3F). This was largely attributed to the volumes of the cortical cortex (r ¼ 0.9877) (Fig. 3F), suggesting that the expansion of the

cerebral cortex is involved in the gyrification reflected by the gyral demarcation of the neocortex at Stage 2 and by the emergences of the secondary and tertiary sulci at Stage 3. As shown in Figure 2E, the mean GI in cynomolgus monkeys seemed to increase continuously after birth. In fact, the average sulcal length and depth reached a respective 80% and 48% of adult values by the 24th week of the 26.5 week-long gestational term in baboon fetuses (Kochounov et al., 2010), while in cynomolgus monkeys, a small change in primary sulcal lengths continued to be observed by at least their postnatal age of 12 months (Sakamoto et al., 2010). A continuous increase in GI values after birth is also observed in humans, while mean GI values reach their maximum during postnatal week

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Fig. 2. Developmental changes in brain weight, volumes of cerebrum, and gyrification index (GI) in cynomolgus monkey fetuses from embryonic days (EDs) 70–150. A. Brain weight (N ¼ 3). B. Mean value of brain weight gain (N ¼ 3). C. Length of frontooccipital line (FO length) (N ¼ 3). D. Volumes of entire cerebrum, cortical gray matter (GM) and subcortical white-matter/intermediate zone (WM/IZ) (N ¼ 6).

E. Mean gyrification index (GI) (N ¼ 6). F. Correlation of each cerebral region with mean GI (N ¼ 6). Volumes of each region correlated closely with mean GI: whole cerebrum, r ¼ 0.9797; cortical GM, r ¼ 0.9877; white matter/intermediate zone, r ¼ 0.8961 [adapted from Fukunishi et al. (2006), Kashima et al. (2008), and Sawada et al. (2010)].

38, and then reach a plateau after a small overshoot (Armstrong et al., 1995). Cortical maturation, which is evaluated by decreasing the ratio of the volume of the cortical gray matter to that of the subcortical white matter, continues during postnatal development (Gogtay et al., 2004). In our previous study, the intensity of T1-weighted MRI signals began to increase in both the cerebral cortex and the subcortical white matter from

ED 140 (Sawada et al., 2012). Such increasing T1weighted MRI signals predict maturations of the cortical gray matter by a decline in the water content of the extracellular matrix and an increasing cell-density (Prayer et al., 2006), a myelination of the white matter by shortening of T1 (longitudinal relaxation time) and T2 (transverse relaxation time) (Holland et al., 1986), reduced water diffusion (Sakuma et al., 1991; Nomura


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Fig. 3. Developmental changes in frontoparietal and occipital regions of the cerebrum of cynomolgus monkey fetuses from embryonic days (EDs) 70–150. A. Ratios of lengths of cingulate and calcarine sulci to length of frontooccipital line (FO length) (N ¼ 3). Relative lengths of these sulci are known to reflect the size of frontoparietal

and occipital regions of the primate cerebrum, respectively. B. Mean gyrification index (GI) in frontoparietal region (anterior to the genu of the corpus callosum) and the occipital region (posterior to the splenium of the corpus callosum) (N ¼ 6) [adapted from Fukunishi et al. (2006) and Sawada et al. (2010)].

et al., 1994), and increased diffusion anisotropy (Neil et al., 1998). Therefore, the progression of gyrification after birth (Stage 4 of the gyrification processes) may reflect the growth of the sulcal length and depth accompanied by cortical maturations.

may be attributed to forming the characteristic GI distribution pattern of catarrhines. Thus, the more frequent GIs in the occipital region than in the frontoparietal region of the cerebrum of cynomolgus monkeys became evident during EDs 120-150. However, as mentioned earlier, cerebral growth evaluated by the relative lengths of cingulate and calcarine sulci was greater in the frontoparietal region than in the occipital region. These results suggest that the gyrification is not correlated with cerebral growth at Stage 3. Yet, such results are inconsistent with previous studies in humans, which have revealed a correlation between the overall growth of the brain and the GI (Pillay and Manger, 2007; Armstrong et al., 1991). To resolve those inconsistencies, we needed to characterize which types of sulci alter the GI values in each region of the cynomolgus monkey cerebrum during EDs 120–150. In our previous studies, small sulci and dimples recognizing secondary and tertiary sulci were generated during EDs 120 and 150, largely in the frontal lobe, somewhat less in the parietal and temporal lobes, and very infrequently in the occipital lobe of cynomolgus monkeys (Fukunishi et al., 2006; Kashima et al., 2008; Sawada et al., 2010, 2012). Therefore, the increased GI values during EDs 120–150 in cynomolgus monkeys may be closely related to the progression of sulcal infolding in the occipital region, and to the generation of secondary and tertiary sulci in the frontoparietal region in the cerebrum of cynomolgus monkey fetuses. Thus, at Stage 3 of the gyrification processes, GI values may be altered by the types of cerebral sulci rather than by their cerebral growth. When the development of the rostrocaudal GI distribution of the cerebrum among humans (Dubois et al., 2008) and cynomolgus monkeys (Sawada et al., 2010) is compared, the pattern is homologous phylogenetically among those two primates. The interspecies difference in the GI distribution became evident by the progression of the cortical infolding of the frontal region in humans. The frontal region of the primate cerebrum is known to include the prefrontal cortex specialized for cognition (Miller and Wallis, 2003). That, therefore, suggested

REGIONAL DIFFERENCES IN CEREBRAL GROWTH AND GYRIFICATION The regional differences in cerebral growth and gyrification were estimated in cynomolgus monkey fetuses. The cerebrum was roughly divided into two regions, that is, the frontoparietal (anterior to the genu of the corpus callosum) and the occipital (posterior to the splenium of the corpus callosum) regions. The frontoparietal region includes the frontal lobe, the anterior part of the parietal lobe and the limbic cortex, while the occipital region includes the posterior part of the parietal and the occipital lobes, respectively. As an index of cerebral growth, we used ratios of the lengths of cingulate and calcarine sulci to the FO-length. Such relative lengths of those sulci are known to reflect the size of the frontoparietal and occipital regions of the primate cerebrum, respectively (Imagawa and Yamadori, 1986). The relative length of the cingulate sulcus exhibited a biphasic increase during its development, that is, a slowly increasing phase from EDs 90 to 110, a rapidly increasing phase from EDs 110 to 130, then reaching a plateau by ED 140 (Fig. 3A). In contrast, the relative length of the calcarine sulcus increased linearly from ED 90, reaching a plateau on ED 130 (Fig. 3A). GI values in the frontoparietal and occipital regions of cynomolgus monkey fetuses were also estimated. GI values in each region began to increase from ED 100, whereas greater GI values in the occipital region than in the frontoparietal region were noted on ED120 and thereafter (Fig. 3B). Because the rostrocaudal patterns of gyrification are specific to each mammalian species (Zilles et al., 1988, 1989; Wosinski et al., 1996; Pillay and Manger, 2007; Sawada et al., 2010), a drastic increase in GI values in the occipital region from ED120

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Fig. 4. Summary of concept of gyrification processes in primates.

that the progression of sulcal infolding in the prefrontal cortex at Stage 3 of the gyrification processes is one of the anatomical characteristics of the cortical organizations acquired in humans as a phylogenetical specification.

RELATION BETWEEN DEVELOPMENTS OF CEREBRAL SULCI AND SUBCORTICAL FIBER TRACTS As mentioned in the ‘‘Proposed developmental stages of gyrification processes’’ section, the volume of cortical gray matter exhibited a pattern similar to that of an increase to the mean GI, and was closely correlated with the GI values (r ¼ 0.9877) in cynomolgus monkey fetuses (Fig. 3D). In contrast, the volume of the subcortical white matter/intermediate zone increased gradually with increasing embryonic days, reaching a plateau by ED 120 in cynomolgus fetuses (Fig. 3D). The increasing phase of the volume of the subcortical white matter/intermediate zone corresponded to Stages 1 and 2 of the gyrification processes. The high correlation between the GI and the white matter/intermediate zone volume (r ¼ 0.8961) should also be noted (Sawada et al., 2010). There is evidence suggesting that the gyrification is influenced by the degree of cortical connectivity, that is, its underlying corticocortical (Van Essen, 1997) and thalamocortical connections (Rackic, 1988). A correlation of the sulcal infolding progression with a radial expansion of the cortical surface was also reported (Smart and McSherry, 1986a,b; Kroenke et al., 2007). By contrast, contribution of the white matter myelination with gyrification was

not revealed by either histological or conventional MRI studies in the developing cerebrum of ferrets (Neil et al., 2006). Therefore, the gyrification may be correlated with both the cortical expansion and the increase of cortical connectivity, but not with myelination of the subcortical white matter. Several hypotheses have been reported in terms of the mechanism of gyrification, that is, genetic control (Rakic, 2004), differential growth of inner and outer cortical strata (Richman et al., 1975), cortical growth (Toro and Burnod., 2005) and tension from white matter axons (van Essen, 1997; Hilgetag and Barbas, 2005, 2006). Recently, Herculano-Houzel et al. (2010) proposed an extension of Van Essen’s tension-based theory of gyrification that axonal tension by increasing connectivity in the subcortical white matter pulled down on the adjacent cortical gray matter. Our ex vivo diffusion tensor imaging (DTI) study supports their hypothesis. The primary sulcal formation was spatiotemporally related to the emergence of long associative fiber tracts in cynomolgus monkey fetuses at Stages 1 and 2 of the gyrification process (Sawada et al., 2011): unicinate fibers were observed running along the indentation of the lateral fissure rostrocaudally on ED 70; the inferior longitudinal fasciculus emerged together with superior temporal sulcus on ED 80 and that of the lunate sulcus on ED 120; the superior longitudinal fasciculus appeared throughout the frontoparietal region, along with the emergence of the parietooccipital sulcus on ED 80 and those of the arcuate and central sulci on ED 90 (Sawada et al., 2011). Likewise, primary sulci such as the parietooccipital, olfactory and central sulci are formed in


human fetuses during gestational weeks 15–20 (Stage 1 of the gyrification processes), simultaneous with the stage in the development of the corticocortical associative fiber tracts (Huang et al., 2009). Therefore, the emergence of the primary sulci may be involved in an interaction between cerebral expansion and the tension from the white matter brought about by the development of specific corticocortical long associative fiber tracts at Stages 1 and 2 of the gyrification processes.

CONCLUSIONS The previous studies revealed the great contributions of heritability to the morphology of the earlier-appearing sulci, whereas the environmental factors are key factors in the morphology of the later-generating sulci (Cheverud et al., 1990; Lohmann et al., 1999; Lohmann et al., 2008; Kochunov et al., 2010). Furthermore, a certain sex difference in the primary sulcal lengths was reported in cynomolgus monkeys (Imai et al., 2011). Thus, gyrification may be controlled by a number of different genetic, environmental and developmental factors with complex relations. This article proposes a new concept with regard to the gyrification processes of primate species that consist of four stages influenced by different developmental events of the cerebrum (summarized in Fig. 4). Interestingly, those gyrification stages are closely related to the order of the phylogenetical development of the cerebral cortex (Kashima et al., 2008). Nonprimate mammals such as dogs (Wosinski et al., 1996), cats (Ferrer et al., 1988), and ferrets (Smart and McSherry, 1986a) also have the gyrencephalic cerebrum, while their sulcal patterns are different from those in primates. However, it is unclear whether the developmental trajectory of the gyrification is homologous with primates or species-dependent. It will be necessary to examine the gyrification processes based on a relationship between the cerebral growth and the patterns of cortical convolution in nonprimate mammals. Our new concept of gyrification stages may prove helpful in understanding not only the gyrification mechanisms but also the evolution of the cerebral cortical organization itself.

ACKNOWLEDGEMENTS The authors thank Ms. Misaki Watanabe of the Department of Nursing, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Ibaraki, Japan, for her generous assistance.

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