Abstract

Contemporary studies recognize 3 distinct cytoarchitectural and functional areas within the Brodmann area 8 complex, in the caudal prefrontal cortex: 8b, 8aD, and 8aV. Here, we report on the quantitative characteristics of the cortical projections to these areas, using injections of fluorescent tracers in marmoset monkeys. Area 8b was distinct from both 8aD and 8aV due to its connections with medial prefrontal, anterior cingulate, superior temporal polysensory, and ventral midline/retrosplenial areas. In contrast, areas 8aD and 8aV received the bulk of the projections from posterior parietal cortex and dorsal midline areas. In the frontal lobe, area 8aV received projections primarily from ventrolateral areas, while both 8aD and 8b received dense inputs from areas on the dorsolateral surface. Whereas area 8aD received the most significant auditory projections, these were relatively sparse, in comparison with those previously reported in macaques. Finally, area 8aV was distinct from both 8aD and 8b by virtue of its widespread input from the extrastriate visual areas. These results are compatible with a homologous organization of the prefrontal cortex in New and Old World monkeys, and suggest significant parallels between the present pathways, revealed by tract-tracing, and networks revealed by functional connectivity analysis in Old World monkeys and humans.

Introduction

The anatomical descriptor “dorsolateral prefrontal cortex” is usually employed to refer to Brodmann's areas 9, 46, and 8, as well as portions of the frontopolar area 10 (Petrides and Pandya 1999). The functional anatomy of this part of the brain is a topic of interest for both basic and clinical neuroscientists, due to its key role in cognitive function. Whereas it is clear that many functional subdivisions exist, there is an ongoing need for research aimed at refining our knowledge of the anatomical–structural bases of the specific contributions of different cortical areas to behaviors. This knowledge is important for understanding how disruption of different neural pathways by disease or trauma is likely to affect cognition and mental health.

Since its original definition by Brodmann (1909), area 8 (BA8), in the caudal part of the dorsolateral prefrontal cortex, has been the subject of many revisions, which have prompted its parcellation based on cytoarchitectural, connectional, and functional criteria (e.g., Vogt and Vogt 1919; Walker 1940; see Petrides and Pandya 1999 for historical review). Modern studies in primates have proposed that BA8 contains at least 3 distinct cytoarchitectonic subdivisions, arranged in mediolateral succession (Barbas and Pandya 1989; Pandya and Yeterian 1996; Petrides and Pandya 1999; Burman et al. 2006; Burman and Rosa 2009a). Reflecting these earlier findings, and the conclusions of the present study, we refer to these subdivisions as areas, and regard BA8 as a complex.

The current nomenclature for the areas forming BA8 is centered on a prime distinction between lateral and medial portions of this complex (designated areas 8A and 8B by Walker 1940), and further evidence that Walker's area 8A contains anatomically and functionally distinct dorsal and ventral subdivisions (Petrides and Pandya 1999; Burman et al. 2006). In the present paper, we designate these areas using the abbreviations proposed by a recent review of the cortical organization in the marmoset monkey (Callithrix jacchus), which is the animal model used in the present investigation: the medial subdivision of BA8 will be abbreviated as area 8b, whereas the dorsal and ventral subdivisions of lateral area 8 will be referred to as areas 8aD and 8aV, respectively (Paxinos et al. 2012). Putative homologs of these areas have been observed in human autopsy materials (Petrides and Pandya 1999).

Despite the histological similarities, the homology of the areas encompassed within BA8 across primate species requires further investigation. In macaques and marmosets, the pattern of connections between extrastriate cortex and the frontal lobe converges to suggest that area 8aV overlaps, at least in part, with the frontal eye field (Petrides and Pandya 1999; Burman et al. 2006; see also Huerta et al. 1987, for comparable data in squirrel and owl monkeys). However, there is some doubt as to whether the frontal eye field in humans corresponds to area 8aV (Paus 1996; Schmitt et al. 2005). The homology and functions of areas 8aD and 8b remain even less well characterized.

The present study is part of a research program aimed at understanding the organization of the cerebral cortex in the marmoset, a small monkey which has become increasingly important for studies of cognitive function and dysfunction (e.g., Ridley et al. 2001; Pryce et al. 2004; Clarke et al. 2005, 2007, 2011; De Souza Silva et al. 2006; Spinelli et al. 2006; Roberts et al. 2007; Reekie et al. 2008; Philippens et al. 2010; Agustín-Pavón et al. 2012). Previous studies in this species have already established that, as in the macaque and human, BA8 is heterogeneous (Burman et al. 2006; Roberts et al. 2007; Rosa et al. 2009). However, there has been no systematic comparison of the connections of 8aD, 8aV, and 8b, which we regard as a necessary step toward validation of these areas as homologous to their putative counterparts in other primates, and toward a firmer understanding of their functions. In the context of understanding the anatomy and functions of BA8, the marmoset provides an interesting contrast with the more widely used macaque monkey, in having a much smaller, lissencephalic brain, in which the putative homologs of 8aD, 8aV, and 8b are readily accessible on the dorsolateral surface of the frontal lobe (Burman et al. 2006). Understanding the constant and variable connectional features of these areas across primate species will also help to clarify the evolutionary history of the caudal prefrontal cortex, and contribute to the establishment of criteria for definition of the homologous fields in the human brain through functional connectivity and tractography analyses.

Materials and Methods

Tracer Injections

Fluorescent tracers were injected unilaterally in the caudal prefrontal cortex of 6 adult marmosets (C. jacchus). Relevant subject- and injection-specific data are provided in Table 1. The experiments conformed to the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and were approved by the Monash University Animal Experimentation Ethics Committee.

Table 1

Characteristics of the animals and injection sites

Case Sex Weight (g) Hemisphere Tracer Area Diameter (µm)a Survival (days) Labeled neurons (n)b 
CJ74 350 FB 8b 650 10 604 
CJ83 330 DY 8b 700 14 8418 
CJ70 305 FR 8aD 450 14 354 
CJ108 383 FR 8aD (Two deposits) 450, 400 16 1234 
CJ75 405 DY 8aV 950 10 5937 
CJ94 397 DY 8aV, 45 700 14 14 412 
CJ108 383 FE 8aV 400 16 2763 
Case Sex Weight (g) Hemisphere Tracer Area Diameter (µm)a Survival (days) Labeled neurons (n)b 
CJ74 350 FB 8b 650 10 604 
CJ83 330 DY 8b 700 14 8418 
CJ70 305 FR 8aD 450 14 354 
CJ108 383 FR 8aD (Two deposits) 450, 400 16 1234 
CJ75 405 DY 8aV 950 10 5937 
CJ94 397 DY 8aV, 45 700 14 14 412 
CJ108 383 FE 8aV 400 16 2763 

a Estimate based on the maximum mediolateral spread observed across multiple sections, following projection to the layer 4 along radial cell columns.

b Only extrinsic connections included.

The procedures were slightly modified from those described in previous reports from this laboratory (e.g., Reser et al. 2009; Burman, Reser, Richardson, et al. 2011). Each animal was pre-medicated with intramuscular (i.m.) injections of atropine (0.2 mg/kg) and diazepam (2 mg/kg), and anesthetized 20–30 min later with alfaxalone (10 mg/mL, i.m.). Dexamethasone (0.3 mg/kg, i.m.) and amoxicillin (50 mg/kg, i.m.) were administered, following which the animal was placed in a stereotaxic frame. Body temperature, heart rate, and PO2 were continually monitored, and supplemental doses of anesthetic were administered as necessary to maintain an areflexic state. A craniotomy was made over the frontal lobe, and the dura mater was incised. Tracers were aimed at different areas using stereotaxic coordinates (Burman and Rosa 2009a). The exact placement of each tracer injection relative to distinct cytoarchitectural fields was determined later, by post-mortem reconstruction. To maximize the experimental value of each animal, and to ensure the highest probability of correct placement in the target areas, multiple tracer injections were performed in each animal. Injections that were centered in other areas will be reported separately.

The fluorescent tracers fluororuby (FR; dextran-conjugated tetramethylrhodamine, molecular weight 10 000), fluoroemerald (FE; dextran-conjugated fluorescein, molecular weight 10 000), fast blue (FB), and diamidino yellow (DY) were injected using a 1 µL microsyringe fitted with a fine glass micropipette tip (see Table 1 for details). Each tracer was injected over 15–20 min, with small deposits of tracer (0.02 µL each) made at different depths. Following the last deposit (typically at a depth of 300 µm), the pipette was left in place for 3–5 min to minimize tracer reflux. Examples of injection sites in areas 8aV, 8aD, and 8b are illustrated in Figure 1, and estimates of the diameter of each injection site are given in Table 1. After the injections, the surface of the brain was covered with moistened ophthalmic film, over which the dural flaps were carefully arranged. The excised bone fragment was repositioned and secured in place with dental acrylic, and the wound closed in anatomical layers. Postoperative analgesics were administered immediately after the animal exhibited spontaneous movements (Temgesic 0.01 mg/kg, i.m.), and for the following 2–3 days (Carprofen 4 mg/kg, subcutaneous).

Figure 1.

Examples of injection sites. Whereas examination of a single section only reveals part of the trajectory, these series of photomicrographs demonstrate the restricted lateral spread of the injection sites, and confirm that the white matter was not involved. (Left) Injection site in area 8b in case CJ83-DY. The photographs of the injection site (top two panels) were obtained in sections counterstained for myelin. The bottom panel illustrates a Nissl-stained section adjacent to the section where the injection site made the closest approach to the interface between cortex and white matter (A + 14.8). (Middle) Injection sites in area 8aD in case CJ108-FR. In this case, tracer was released along two parallel tracks, both of which were confined to area 8aD. Again, the Nissl-stained section (A + 14.6) corresponds to the level where the injection site was deemed closest to the white matter. (Right) Injection site in area 8aV in case CJ108-FE. This series of sections demonstrates that the injection site reached at least to layer 5 in this case; unfortunately, the section where the injection site was deemed deepest (A + 15.3) was damaged subsequent to plotting. Scale bars: 1 mm.

Figure 1.

Examples of injection sites. Whereas examination of a single section only reveals part of the trajectory, these series of photomicrographs demonstrate the restricted lateral spread of the injection sites, and confirm that the white matter was not involved. (Left) Injection site in area 8b in case CJ83-DY. The photographs of the injection site (top two panels) were obtained in sections counterstained for myelin. The bottom panel illustrates a Nissl-stained section adjacent to the section where the injection site made the closest approach to the interface between cortex and white matter (A + 14.8). (Middle) Injection sites in area 8aD in case CJ108-FR. In this case, tracer was released along two parallel tracks, both of which were confined to area 8aD. Again, the Nissl-stained section (A + 14.6) corresponds to the level where the injection site was deemed closest to the white matter. (Right) Injection site in area 8aV in case CJ108-FE. This series of sections demonstrates that the injection site reached at least to layer 5 in this case; unfortunately, the section where the injection site was deemed deepest (A + 15.3) was damaged subsequent to plotting. Scale bars: 1 mm.

Tissue Processing

Survival times were between 10 and 16 days (Table 1), after which the animals were anesthetized with alfaxalone (10 mg/mL, i.m.) and, following loss of consciousness, administered an overdose of sodium pentabarbitone (100 mg/kg, i.v.). They were then immediately perfused through the heart with 1-L heparinized saline, followed by 1 L 4% paraformaldehyde in 0.1 M phosphate-buffered saline (pH 7.4). The brains were postfixed in the same medium for at least 24 h, and then immersed in buffered paraformaldehyde with increasing concentrations of sucrose (10–30%). They were then sectioned (40 µm thickness) in the coronal plane, using a cryostat. One section in 5 was mounted unstained for examination of fluorescent tracers, and coverslipped with dinbutyl phthalate xylene after quick dehydration (2× 100% ethanol) and defatting (2× xylene). Adjacent sections were stained for Nissl substance, cytochrome oxidase, and myelin, following standard protocols (Gallyas 1979; Wong-Riley 1979). The remaining section in each series was stored in cryoprotectant solution in a freezer, to be used as a backup in case of unsatisfactory staining or damage during processing of the histological sections.

Data Analysis

Sections were examined using Zeiss Axioplan 2 or Axioskop 40 epifluorescence microscopes. Labeled neurons were identified using ×10 or ×20 dry objectives, and their locations within the cortex and subcortical structures were mapped using a digitizing system (MD Plot3, Accustage) attached to the microscope. To minimize the problem of overestimating the number of neurons due to inclusion of cytoplasmic fragments, labeled cells were accepted as valid only if a nucleus could be discerned. This was straightforward in the case of DY, as this tracer only labels the neuron's nucleus (Keizer et al. 1983). In the case of tracers that label the cytoplasm (FB, FE, and FR), the nucleus was discerned as a profile in the center of a brightly lit, well-defined cell body, which in the vast majority of cases had an unmistakable pyramidal morphology (e.g., Supplementary Fig. S1). The entire brain was scanned in the examined series (1 in 5 sections), and every labeled neuron was plotted. In all cases, attribution of the injection sites and labeled cells to a specific cortical area was based on examination of histological sections from the same animal, using the cytoarchitectural patterns illustrated by Paxinos et al. (2012) as a guide. Examples of these borders are shown in Figures 6–9. Whereas we also identify in the figures the locations of the main groups of subcortical labeled neurons, these were not quantitatively analyzed as part of the present study.

The extents of the DY or FB injection sites were estimated according to the criteria defined by Condé (1987). In our illustrations, these injection sites are represented as 2 concentric zones: a dark region, indicating the combined extent of Condé's zones 0 and 1 (hence corresponding to a generous estimate of the tracer uptake zone), and a light region, corresponding to zones 2 and 3 (where the cytoarchitecture was disrupted, but no tracer uptake was expected). In illustrations of FR and FE injections, the dark region indicates cortex containing fluorescent dye in the extracellular space (i.e., limited to the neighborhood of the needle track; Schmued et al. 1990), and the light region indicates the surrounding zone where virtually every cell body was brightly labeled.

To visualize the distribution of labeled neurons throughout the entire cortex, 3-dimensional (3D) and 2-dimensional (2D) computer graphic reconstructions were prepared. Nissl-stained sections were scanned into digital images and sequentially aligned with the StackReg plug-in (Thévenaz et al. 1998) for ImageJ (Abramoff et al. 2004) to create a 3D volume. The alignment was refined using a publicly available stereotaxic magnetic resonance imaging (MRI) atlas of the marmoset (Newman et al. 2009) as a template. Using the brain mapping program ANTS (Avants et al. 2008), the 3D MRI template volume was aligned to the 3D histological volume using an affine transformation, so that the MRI volume was now in the same coordinate space as the histological volume. Each histological section was subsequently aligned to its corresponding MRI section using an affine transformation.

To create the 2D surface models, cortical layer 4 was manually traced using ImageJ to create a series of contours that were reconstructed into a 3D triangular mesh, using the program CARET (Van Essen et al. 2001). The mesh was then re-sampled and smoothed with MeshLab (Cignoni et al. 2008). The coordinates of labeled neurons were extracted from MDPlot data files and projected to the nearest polygon in the mesh, following which the 3D surface was computationally flattened using CARET.

A full list of the abbreviations of cortical areas that contained labeled neurons following the present injections is presented in Table 2. In all figures, the sections and maps are illustrated using the appropriate convention for the right hemisphere, to facilitate comparisons between cases and with earlier publications from our laboratory. The actual hemisphere in which the injections were placed is given for each case in Table 1.

Table 2

Abbreviations of cortical areas that contained labeled neurons in the present study

Abbreviation Designation Equivalent designation(s) in other studies, and notes 
1/2 Cytoarchitectural areas 1 and 2  
3a Area 3a  
Area 4 Primary motor area (M1, Burman et al. 2008); caudal subdivision of the primary motor area (M1c; Stepniewska et al. 1993
6DC Area 6 dorsocaudal Rostral subdivision of the primary motor area (M1r; Stepniewska et al. 1993
6DR Area 6 dorsorostral Dorsal premotor area (PMd; Stepniewska et al. 1993
6M Area 6 medial Supplementary motor area (Stepniewska et al. 1993
6V Area 6 ventral Ventral premotor area (Stepniewska et al. 1993
8aD Area 8a dorsal  
8aV Area 8a ventral  
8C Area 8 caudal Densely myelinated subregion of dorsal area 6 (6d*; Burman et al. 2006
Area 9  
10 Area 10  
11 Area 11  
12L Area 12 lateral Area 47L (Paxinos et al. 2012
12M Area 12 medial Area 47M (Paxinos et al. 2012
12O Area 12 orbital Area 47O (Paxinos et al. 2012
13a/b Area 13, subdivisions a and b  
13L Area 13 lateral  
13M Area 13 medial  
14 Area 14 Includes rostral and caudal subdivisions (Burman and Rosa 2009a,b
19M Area 19, medial Medial visual area (M; Rosa and Schmid 1995
23a Area 23, subdivision a  
23b/c Area 23, subdivisions b and c  
23V Area 23, ventral  
24a Area 24, subdivision a  
24b Area 24, subdivision b  
24c/d Area 24, subdivisions c and d Area 24d is likely to correspond to the caudal cingulate motor area (Dum and Strick 1996
29a–d Area 29, subdivisions a, b, c, and d  
30 Area 30  
31 Area 31 Caudal part of the medial dorsal parietal area (MDP; Rosa et al. 2009
32V Area 32 ventral Medial caudal area 10 (10 mc; Burman and Rosa 2009a; Burman, Reser, Yu, et al. 2011
36 Area 36 Lateral perirhinal cortex 
45 Area 45 Dorsal part of area 12/45 (Burman et al. 2006
46D Area 46 dorsal  
46V Area 46 ventral Area 46 (Burman et al. 2006
AIP Anterior intraparietal area  
CPB Caudal parabelt Area PBc (Burman, et al. 2011a
DA(V3A) Dorsoanterior visual area Corresponds to visual area 3A (V3A) of Old World monkeys (Paxinos et al. 2012
DI Dorsointermediate visual area  
DM(V6) Dorsomedial area Sixth visual area (V6; Rosa and Tweedale 2001
FST Fundus of the superior temporal sulcus area Dorsal subdivision of the fundus of the superior temporal area (FSTd; Kaas and Morel 1993
Gu Gustatory cortex G (Burman and Rosa 2009a
LIP Lateral intraparietal area  
MIP Medial intraparietal area  
MST Medial superior temporal area  
MT Middle temporal area Fifth visual area (V5) 
MTC Middle temporal crescent Fourth visual area, transitional (V4T; Paxinos et al. 2012
OPal Orbital paleocortex Medial orbital insular cortex (Ins m; Burman and Rosa 2009a,b
OPro Orbital proisocortex Lateral orbital insular cortex (Ins l; Burman and Rosa 2009a,b
OPt Occipitoparietal transition area Dorsal occipitotemporal area (DOT; Rosa and Tweedale 2000
PE Cytoarchitectural area PE Area 5 
PEC Cytoarchitectural area PE caudal Area PEc (Burman et al. 2008
PF Cytoarchitectural area PF  
PFG Cytoarchitectural area PFG  
PG Cytoarchitectural area PG  
PGM Cytoarchitectural area PG medial Rostral part of the MDP area (Rosa et al. 2009
PGa/IPa Cytoarchitectural areas PGa and IPa of Seltzer and Pandya (1978) Ventral subdivision of the fundus of the superior temporal area (FSTv; Kaas and Morel 1993
PR Parietal rostral area S2PR (Paxinos et al. 2012
PrCO Precentral opercular cortex Proisocortical motor region (ProM; Paxinos et al. 2012
ProSt Area prostriata Area 30v (Kobayashi and Amaral 2000
PV Parietal ventral area S2PV (Paxinos et al. 2012
RPB Rostral parabelt Area PBr (Burman, Reser, Yu, et al. 2011
S2 Second somatosensory area Includes the internal (S2I) and external (S2E) subdivisions of S2 recognized by Paxinos et al. (2012) 
STP Superior temporal polysensory cortex Temporo-parietal-occipital association cortex (TPO; Paxinos et al. 2012
STR Superior temporal rostral association cortex  
TE1 Cytoarchitectural area TE, subdivision 1 Rostral inferior temporal area (ITr; Burman, Reser, Yu, et al. 2011
TE2 Cytoarchitectural area TE, subdivision 2 Ventral inferior temporal area (ITv; Burman, Reser, Yu, et al. 2011
TE3 Cytoarchitectural area TE, subdivision 3 Dorsal inferior temporal area (ITd; Burman, Reser, Yu, et al. 2011
TEO Cytoarchitectural area TE, occipital transition subdivision Caudal inferior temporal area (ITc; Burman, Reser, Yu, et al. 2011
TF Cytoarchitectural area TF Rostrolateral part of cytoarchitectural field TF (Palmer and Rosa 2006a
TFO Cytoarchitectural field TF, occipital transition subdivision Caudolateral part of cytoarchitectural field TF (Palmer and Rosa 2006a
TH Cytoarchitectural area TH  
TL Cytoarchitectural area TL Rostromedial part of cytoarchitectural field TF (Palmer and Rosa 2006a
TLO Cytoarchitectural field TL, occipital transition subdivision Caudomedial part of cytoarchitectural field TF (Palmer and Rosa 2006a
TPPro Temporal pole proisocortex Temporal pole (TP; Burman, et al. 2011a
TPt Temporoparietal transition area  
V2 Second visual area  
V6A Visual area 6A Medial subdivision of the posterior parietal cortex (PPm; Burman et al. 2008
VLA (V4) Ventrolateral anterior area Fourth visual area (V4; Piñon et al. 1998
VLP(V3) Ventrolateral posterior area Third visual area (V3; Rosa et al. 2000
VIP Ventral intraparietal area  
Abbreviation Designation Equivalent designation(s) in other studies, and notes 
1/2 Cytoarchitectural areas 1 and 2  
3a Area 3a  
Area 4 Primary motor area (M1, Burman et al. 2008); caudal subdivision of the primary motor area (M1c; Stepniewska et al. 1993
6DC Area 6 dorsocaudal Rostral subdivision of the primary motor area (M1r; Stepniewska et al. 1993
6DR Area 6 dorsorostral Dorsal premotor area (PMd; Stepniewska et al. 1993
6M Area 6 medial Supplementary motor area (Stepniewska et al. 1993
6V Area 6 ventral Ventral premotor area (Stepniewska et al. 1993
8aD Area 8a dorsal  
8aV Area 8a ventral  
8C Area 8 caudal Densely myelinated subregion of dorsal area 6 (6d*; Burman et al. 2006
Area 9  
10 Area 10  
11 Area 11  
12L Area 12 lateral Area 47L (Paxinos et al. 2012
12M Area 12 medial Area 47M (Paxinos et al. 2012
12O Area 12 orbital Area 47O (Paxinos et al. 2012
13a/b Area 13, subdivisions a and b  
13L Area 13 lateral  
13M Area 13 medial  
14 Area 14 Includes rostral and caudal subdivisions (Burman and Rosa 2009a,b
19M Area 19, medial Medial visual area (M; Rosa and Schmid 1995
23a Area 23, subdivision a  
23b/c Area 23, subdivisions b and c  
23V Area 23, ventral  
24a Area 24, subdivision a  
24b Area 24, subdivision b  
24c/d Area 24, subdivisions c and d Area 24d is likely to correspond to the caudal cingulate motor area (Dum and Strick 1996
29a–d Area 29, subdivisions a, b, c, and d  
30 Area 30  
31 Area 31 Caudal part of the medial dorsal parietal area (MDP; Rosa et al. 2009
32V Area 32 ventral Medial caudal area 10 (10 mc; Burman and Rosa 2009a; Burman, Reser, Yu, et al. 2011
36 Area 36 Lateral perirhinal cortex 
45 Area 45 Dorsal part of area 12/45 (Burman et al. 2006
46D Area 46 dorsal  
46V Area 46 ventral Area 46 (Burman et al. 2006
AIP Anterior intraparietal area  
CPB Caudal parabelt Area PBc (Burman, et al. 2011a
DA(V3A) Dorsoanterior visual area Corresponds to visual area 3A (V3A) of Old World monkeys (Paxinos et al. 2012
DI Dorsointermediate visual area  
DM(V6) Dorsomedial area Sixth visual area (V6; Rosa and Tweedale 2001
FST Fundus of the superior temporal sulcus area Dorsal subdivision of the fundus of the superior temporal area (FSTd; Kaas and Morel 1993
Gu Gustatory cortex G (Burman and Rosa 2009a
LIP Lateral intraparietal area  
MIP Medial intraparietal area  
MST Medial superior temporal area  
MT Middle temporal area Fifth visual area (V5) 
MTC Middle temporal crescent Fourth visual area, transitional (V4T; Paxinos et al. 2012
OPal Orbital paleocortex Medial orbital insular cortex (Ins m; Burman and Rosa 2009a,b
OPro Orbital proisocortex Lateral orbital insular cortex (Ins l; Burman and Rosa 2009a,b
OPt Occipitoparietal transition area Dorsal occipitotemporal area (DOT; Rosa and Tweedale 2000
PE Cytoarchitectural area PE Area 5 
PEC Cytoarchitectural area PE caudal Area PEc (Burman et al. 2008
PF Cytoarchitectural area PF  
PFG Cytoarchitectural area PFG  
PG Cytoarchitectural area PG  
PGM Cytoarchitectural area PG medial Rostral part of the MDP area (Rosa et al. 2009
PGa/IPa Cytoarchitectural areas PGa and IPa of Seltzer and Pandya (1978) Ventral subdivision of the fundus of the superior temporal area (FSTv; Kaas and Morel 1993
PR Parietal rostral area S2PR (Paxinos et al. 2012
PrCO Precentral opercular cortex Proisocortical motor region (ProM; Paxinos et al. 2012
ProSt Area prostriata Area 30v (Kobayashi and Amaral 2000
PV Parietal ventral area S2PV (Paxinos et al. 2012
RPB Rostral parabelt Area PBr (Burman, Reser, Yu, et al. 2011
S2 Second somatosensory area Includes the internal (S2I) and external (S2E) subdivisions of S2 recognized by Paxinos et al. (2012) 
STP Superior temporal polysensory cortex Temporo-parietal-occipital association cortex (TPO; Paxinos et al. 2012
STR Superior temporal rostral association cortex  
TE1 Cytoarchitectural area TE, subdivision 1 Rostral inferior temporal area (ITr; Burman, Reser, Yu, et al. 2011
TE2 Cytoarchitectural area TE, subdivision 2 Ventral inferior temporal area (ITv; Burman, Reser, Yu, et al. 2011
TE3 Cytoarchitectural area TE, subdivision 3 Dorsal inferior temporal area (ITd; Burman, Reser, Yu, et al. 2011
TEO Cytoarchitectural area TE, occipital transition subdivision Caudal inferior temporal area (ITc; Burman, Reser, Yu, et al. 2011
TF Cytoarchitectural area TF Rostrolateral part of cytoarchitectural field TF (Palmer and Rosa 2006a
TFO Cytoarchitectural field TF, occipital transition subdivision Caudolateral part of cytoarchitectural field TF (Palmer and Rosa 2006a
TH Cytoarchitectural area TH  
TL Cytoarchitectural area TL Rostromedial part of cytoarchitectural field TF (Palmer and Rosa 2006a
TLO Cytoarchitectural field TL, occipital transition subdivision Caudomedial part of cytoarchitectural field TF (Palmer and Rosa 2006a
TPPro Temporal pole proisocortex Temporal pole (TP; Burman, et al. 2011a
TPt Temporoparietal transition area  
V2 Second visual area  
V6A Visual area 6A Medial subdivision of the posterior parietal cortex (PPm; Burman et al. 2008
VLA (V4) Ventrolateral anterior area Fourth visual area (V4; Piñon et al. 1998
VLP(V3) Ventrolateral posterior area Third visual area (V3; Rosa et al. 2000
VIP Ventral intraparietal area  

Quantification of Tracer Distribution

There are well-known difficulties involved in quantitatively comparing data on anatomical tracer distribution across cases, which may derive from factors such as differences in the transport characteristics of tracers and distribution of tracer across cortical layers, the large number of cortical areas which have no label or single-digit cell counts (relative to the hundreds or thousands of neurons which may be found in areas near the injection site), and differences in the size of the cortical areas targeted by the injections (meaning that even same-sized tracer injections will encompass different fractions of the area's volume). The combination of these factors, and the uncertainty associated with the relatively small samples used in most primate neuroanatomy studies, make it inappropriate to use parametric statistics, as normal distributions of all relevant variables cannot be assumed. Thus, with the aim of producing statistical comparisons of the distribution of label obtained from injections in different areas, we adapted well-characterized non-parametric statistical methods (Siegel 1956), which have been successfully applied to an analogous problem in field ecology (namely, the determination of species association based on the capture frequency of individuals relative to defined areas of the terrestrial environment; Legendre 2005). To accomplish this, we first grouped the approximately 120 architectonic areas of the marmoset neocortex (Paxinos et al. 2012) into a manageable number of anatomically related sectors (Fig. 2, Table 3). This step had the effect of both reducing the dimensionality of the dataset, and partially correcting for areas with zero or low cell counts. We have termed these groupings of areas anatomical “sectors” of the cortex, to avoid confusion with other descriptors (e.g., regions, fields, areas). No labeled neurons were found in olfactory areas following any of the present injections, so further analyses were based on 14 cortical sectors. Using these sectors, we quantitatively assessed the degree of similarity in tracer distribution following injections in the same target areas (a step which implicitly also meant testing this relationship across different animals, and tracers). Reproducibility of the tracer distributions following injections in the same area was assessed using the Spearman rank correlation (RS), which minimizes the effect of large differences in cell counts between cases. To address the concordance (or lack thereof) in the pattern of tracer distribution across the 3 areas, we employed the Kendall coefficient of concordance (W), a computationally simple non-parametric measure which has the advantageous properties of allowing for direct comparison of multiple correlation measures, with straightforward post hoc testing by computation of partial W coefficients (Legendre 2005).

Table 3

Percentages of labeled neurons in different cortical areas

 Injection site 8b
 
8aD
 
8aV
 
8aV/45 

 
Case ID
 
CJ74FB
 
CJ83DY
 
CJ70FR
 
CJ108FR
 
CJ75DY
 
CJ108FE
 
CJ94-DY
 
Sector Cortical area % of total % of total % of total % of total % of total % of total % of total 
Dorsolateral prefrontal (dlp12.7 22.6 15.0 10.5 – – 0.9 
10 3.3 8.2 2.5 1.1 0.2 0.1 0.9 
46 14.8 1.4 7.1 5.2 3.4 5.6 5.5 
8b   8.2 10.5 0.1 0.5 0.1 
8aD 1.8 21.1   0.8 1.8 0.7 
8aV 0.3 1.1 1.1 4.6    
Ventrolateral prefrontal (vlp12L 1.8 0.7 4.0 6.6 36.9 36.9 28.6 
12M 1.3 0.9 0.8 0.2 0.8 1.5 0.9 
12O 0.3 1.5 – – 0.2 1.5 0.2 
45 – – – – 5.3 6.4 8.0 
PrCO – – – – 0.1 0.5 
Orbitofrontal (ofc11 0.2 0.8 4.0 0.9 0.1 – – 
13a/b – – – – 0.1 – 
13L 1.8 2.8 3.2 0.2 0.1 0.4 
13M – 0.2 0.6 0.5 – 0.3 
Gu – – – – – 
OPal – 0.2 – – – – – 
OPro – 0.1 – – – – – 
Medial prefrontal (mpc14 0.2 0.2 – – – – 
32 16.9 7.9 – 0.1 – 
32V – 0.1 – – – – – 
Premotor/motor (prm– – – – – 2.6 
6DC – 4.8 – 0.7 0.5 0.6 3.3 
6DR 4.8 11.5 6.8 11.3 4.3 2.7 8.7 
6M – 1.4 0.8 – 0.1 
6V – 0.8 – 2.5 3.2 6.3 
8C – – – – 0.8 4.7 1.7 
Anterior cingulated (acc24a 4.5 4.1 – 0.3 – – 0.2 
24b 0.8 1.3 1.7 0.2 – 0.1 
24c/d 0.2 0.1 – – – – – 
Somatosensory (ssc3a 0.2 – – – – 0.1 
1/2 – – – – 0.1 0.1 
S2/PV/PR – – 2.0 0.2 
Insular (insAll divisions – 1.4 – 0.2 0.1 
Auditory (audCore + belt – – – – – 
Parabelt 1.0 0.2 0.3 0.1 0.1 – 
TPt – – 4.5 0.7 – 
STR – 0.1 – – – – – 
Lateral and inferior temporal (litTE1 – 0.1 – – – – 0.7 
TE2 – – – – – 0.4 
TE3 0.3 0.2 – – 3.6 0.1 2.7 
TEO – – – – 0.4 – 0.8 
STP 2.5 2.4 1.1 0.1 0.1 – 
PGa/IPa 0.7 0.4 0.8 – 2.2 0.4 1.7 
Ventral temporal (vtc36/TPPro 0.7 – – 0.1 – – 
Ent – – – 0.1 – – 
TF/TL – 0.1 – – – – – 
TH – 0.1 – 0.1 0.1 0.1 – 
TFO/TLO – – 0.3 0.1 0.2 – 
Posterior parietal (ppcAIP – – – – 0.4 2.0 – 
LIP – – 0.1 0.5 1.1 0.5 3.7 
MIP – – – – 1.2 1.5 1.9 
VIP – – – 0.2 – 1.1 – 
PE/PEC – – 0.6 0.7 0.4 5.1 1.8 
PF – – 2.8 0.8 – 2.0 0.4 
PFG 0.1 – – 2.8 1.2 
PG – – 0.5 1.8 0.1 3.3 0.2 
Opt – – – – 0.2 1.6 0.9 
PGM 0.5 0.3 1.1 1.3 0.2 
31 – 0.3 0.9 1.7 0.1 
Posterior cingulate and retrosplenial (pcr29a–d 2.8 2.1 0.6 5.9 0.1 0.3 
30 7.9 2.4 4.0 10.9 0.1 – 0.1 
23a 13.9 1.1 16.7 5.9 0.1 
23b/c 0.8 0.6 6.5 10.2 – 1.7 0.2 
23V 0.5 0.1 – 0.6 0.3 0.2 0.2 
ProSt 3.1 – 0.2 – – 
Visual (visV2 – – – – 1.3 0.6 0.2 
VLP(V3) – – – – 1.7 0.3 0.2 
VLA(V4) – – – 2.9 0.2 2.3 
MT – – – – 4.0 1.4 0.6 
MTC – – – – 4.1 0.1 3.0 
MST – – 0.8 0.2 1.3 2.6 1.3 
FST – 0.3 – 5.1 0.5 1.8 
DM(V6) – – – – 1.7 0.1 0.1 
DA(V3A) – – – – 8.5 0.4 2.4 
DI – – – – 1.7 – 
V6A – – – – – 0.7 – 
19M – – 0.3 0.2 0.8 1.2 0.2 
 Injection site 8b
 
8aD
 
8aV
 
8aV/45 

 
Case ID
 
CJ74FB
 
CJ83DY
 
CJ70FR
 
CJ108FR
 
CJ75DY
 
CJ108FE
 
CJ94-DY
 
Sector Cortical area % of total % of total % of total % of total % of total % of total % of total 
Dorsolateral prefrontal (dlp12.7 22.6 15.0 10.5 – – 0.9 
10 3.3 8.2 2.5 1.1 0.2 0.1 0.9 
46 14.8 1.4 7.1 5.2 3.4 5.6 5.5 
8b   8.2 10.5 0.1 0.5 0.1 
8aD 1.8 21.1   0.8 1.8 0.7 
8aV 0.3 1.1 1.1 4.6    
Ventrolateral prefrontal (vlp12L 1.8 0.7 4.0 6.6 36.9 36.9 28.6 
12M 1.3 0.9 0.8 0.2 0.8 1.5 0.9 
12O 0.3 1.5 – – 0.2 1.5 0.2 
45 – – – – 5.3 6.4 8.0 
PrCO – – – – 0.1 0.5 
Orbitofrontal (ofc11 0.2 0.8 4.0 0.9 0.1 – – 
13a/b – – – – 0.1 – 
13L 1.8 2.8 3.2 0.2 0.1 0.4 
13M – 0.2 0.6 0.5 – 0.3 
Gu – – – – – 
OPal – 0.2 – – – – – 
OPro – 0.1 – – – – – 
Medial prefrontal (mpc14 0.2 0.2 – – – – 
32 16.9 7.9 – 0.1 – 
32V – 0.1 – – – – – 
Premotor/motor (prm– – – – – 2.6 
6DC – 4.8 – 0.7 0.5 0.6 3.3 
6DR 4.8 11.5 6.8 11.3 4.3 2.7 8.7 
6M – 1.4 0.8 – 0.1 
6V – 0.8 – 2.5 3.2 6.3 
8C – – – – 0.8 4.7 1.7 
Anterior cingulated (acc24a 4.5 4.1 – 0.3 – – 0.2 
24b 0.8 1.3 1.7 0.2 – 0.1 
24c/d 0.2 0.1 – – – – – 
Somatosensory (ssc3a 0.2 – – – – 0.1 
1/2 – – – – 0.1 0.1 
S2/PV/PR – – 2.0 0.2 
Insular (insAll divisions – 1.4 – 0.2 0.1 
Auditory (audCore + belt – – – – – 
Parabelt 1.0 0.2 0.3 0.1 0.1 – 
TPt – – 4.5 0.7 – 
STR – 0.1 – – – – – 
Lateral and inferior temporal (litTE1 – 0.1 – – – – 0.7 
TE2 – – – – – 0.4 
TE3 0.3 0.2 – – 3.6 0.1 2.7 
TEO – – – – 0.4 – 0.8 
STP 2.5 2.4 1.1 0.1 0.1 – 
PGa/IPa 0.7 0.4 0.8 – 2.2 0.4 1.7 
Ventral temporal (vtc36/TPPro 0.7 – – 0.1 – – 
Ent – – – 0.1 – – 
TF/TL – 0.1 – – – – – 
TH – 0.1 – 0.1 0.1 0.1 – 
TFO/TLO – – 0.3 0.1 0.2 – 
Posterior parietal (ppcAIP – – – – 0.4 2.0 – 
LIP – – 0.1 0.5 1.1 0.5 3.7 
MIP – – – – 1.2 1.5 1.9 
VIP – – – 0.2 – 1.1 – 
PE/PEC – – 0.6 0.7 0.4 5.1 1.8 
PF – – 2.8 0.8 – 2.0 0.4 
PFG 0.1 – – 2.8 1.2 
PG – – 0.5 1.8 0.1 3.3 0.2 
Opt – – – – 0.2 1.6 0.9 
PGM 0.5 0.3 1.1 1.3 0.2 
31 – 0.3 0.9 1.7 0.1 
Posterior cingulate and retrosplenial (pcr29a–d 2.8 2.1 0.6 5.9 0.1 0.3 
30 7.9 2.4 4.0 10.9 0.1 – 0.1 
23a 13.9 1.1 16.7 5.9 0.1 
23b/c 0.8 0.6 6.5 10.2 – 1.7 0.2 
23V 0.5 0.1 – 0.6 0.3 0.2 0.2 
ProSt 3.1 – 0.2 – – 
Visual (visV2 – – – – 1.3 0.6 0.2 
VLP(V3) – – – – 1.7 0.3 0.2 
VLA(V4) – – – 2.9 0.2 2.3 
MT – – – – 4.0 1.4 0.6 
MTC – – – – 4.1 0.1 3.0 
MST – – 0.8 0.2 1.3 2.6 1.3 
FST – 0.3 – 5.1 0.5 1.8 
DM(V6) – – – – 1.7 0.1 0.1 
DA(V3A) – – – – 8.5 0.4 2.4 
DI – – – – 1.7 – 
V6A – – – – – 0.7 – 
19M – – 0.3 0.2 0.8 1.2 0.2 

Only extrinsic connections are reported; gray cells correspond to the areas where the injections were placed.

The – symbol indicates areas where no labeled neurons were observed.

*The symbol indicates areas where isolated labeled neurons were observed, which accounted for <0.1% of the total extrinsic label.

Figure 2.

Two-dimensional reconstruction of the marmoset cortex, showing the areas defined by Paxinos et al. (2012) grouped into 15 anatomical and functional sectors (colors). This map, representing a right hemisphere (rostral to the right, ventral downwards), was prepared using the software suite CARET (Van Essen et al. 2001). To reduce the amount of distortion, discontinuities were introduced along the frontal pole and ventromedial convexity of the frontal lobe (thus separating portions of areas 10, 14, and 25), the temporal pole, and the fundus of the calcarine sulcus (thus separating portions of the primary visual area, V1 and area prostriata, ProSt). The red and green pairs of asterisks each indicate 2 adjacent points which became separated in the maps due to such discontinuities. Whereas this type of representation allows a global appreciation of the topological relationship between cortical areas, there are significant residual distortions (typically, areal expansion along the edges of the map). Thus, the scale bar (5 mm) is approximate. The abbreviations of areas containing labeled neurons following injections in areas 8aD, 8aV, and 8b are given in Table 2; for other abbreviations, see Paxinos et al. (2012).

Figure 2.

Two-dimensional reconstruction of the marmoset cortex, showing the areas defined by Paxinos et al. (2012) grouped into 15 anatomical and functional sectors (colors). This map, representing a right hemisphere (rostral to the right, ventral downwards), was prepared using the software suite CARET (Van Essen et al. 2001). To reduce the amount of distortion, discontinuities were introduced along the frontal pole and ventromedial convexity of the frontal lobe (thus separating portions of areas 10, 14, and 25), the temporal pole, and the fundus of the calcarine sulcus (thus separating portions of the primary visual area, V1 and area prostriata, ProSt). The red and green pairs of asterisks each indicate 2 adjacent points which became separated in the maps due to such discontinuities. Whereas this type of representation allows a global appreciation of the topological relationship between cortical areas, there are significant residual distortions (typically, areal expansion along the edges of the map). Thus, the scale bar (5 mm) is approximate. The abbreviations of areas containing labeled neurons following injections in areas 8aD, 8aV, and 8b are given in Table 2; for other abbreviations, see Paxinos et al. (2012).

Laminar distribution was analyzed using the proportion of labeled neurons located in the supragranular layers, relative to the total number of labeled neurons in a given area (%SLN; Barone et al. 2000). In the case of areas in which layer 4 was not evident, a similar calculation was performed to express the proportion of neurons located in the putative homologs of layers 2 and 3 (e.g., Kobayashi and Amaral 2000), as a fraction of the total labeled neurons. To avoid bias introduced by small samples, the primary analysis was conducted only on projections that comprised 50 or more neurons, visualized across all cases; this method has been shown previously to reveal the laminar features that are most consistent across cases (Burman, Reser, Yu, et al. 2011). Results obtained using smaller samples are reported in Table 4, but should be taken as provisional, pending further validation. Projections with %SLN ≤ 33 were classified as putative feedback connections, and those with %SLN ≥ 67 were classified as putative feedforward connections. Other projections, formed by nearly balanced numbers of neurons in the supragranular and infragranular layers, were classified as putative lateral connections.

Table 4

Percentages of supragranular neurons in different projections to areas 8b, 8aD, and 8aV

 Area 8b
 
Area 8aD
 
Area 8aV
 
 %SLN Type %SLN Type %SLN Type 
BA8 
 8b 62 64 70 F? 
 8aD 53 57 63 
 8aV 61 69 59 
Dorsolateral prefrontal cortex 
 9 54 63 – – 
 10 61 74 F? – – 
 46 (D, V) 61 74 74 
Ventrolateral prefrontal cortex 
 12L 82 80 83 
 12M 55 – – 57 
 12O 69 – – 56 
 45 – – – – 65 
Orbitofrontal cortex 
 11 71 71 F? 43 L? 
 13 (L, M) 72 F? 70 25 B? 
 Orbital insula 18 B? – – – – 
Medial cortex 
 23 (a–c) 77 87 61 
 23V – – – – 57 L? 
 24 (a, b) 47 92 F? – – 
 29a–d 84 68 – – 
 30 67 87 – – 
 32 40 – – – – 
 ProSt 68 F? – – – – 
Premotor cortex 
 6M 81 – – – – 
 6DC 55 89 F? 45 
 6DR 67 90 51 
 6V – – – – 67 
 8C – – – – 67 
Temporal association cortex 
 Parabelt, TPt 63 L? 85 – – 
 STP, PGa + IPa 68 63 L? 82 
 TE1–TE3 81 F? – – 88 
 Parahippocampal 40 L? – – 19 B? 
Posterior parietal cortex 
 AIP – – – – 68 
 LIP – – – – 57 
 MIP – – – – 42 
 VIP – – – – 61 L? 
 PE, PEC – – 73 F? 75 
 PF – – 80 F? 95 
 PFG 40 L? – – 83 
 PG – – 79 F? 65 
 Opt – – – – 67 
 PGM – – 79 F? 59 L? 
 31 – – 96 91 F? 
Visual cortex 
 V2 – – – – 92 
 VLP(V3) – – – – 79 
 VLA(V4) – – – – 78 
 MT – – – – 72 
 MTC – – – – 78 
 MST – – – – 77 
 FST – – – – 74 
 DM(V6) – – – – 68 
 DA(V3A) – – – – 62 
 DI – – – – 67 
 V6A – – – – 95 F? 
 19M – – – – 67 
 TEO – – – – 92 F? 
 Area 8b
 
Area 8aD
 
Area 8aV
 
 %SLN Type %SLN Type %SLN Type 
BA8 
 8b 62 64 70 F? 
 8aD 53 57 63 
 8aV 61 69 59 
Dorsolateral prefrontal cortex 
 9 54 63 – – 
 10 61 74 F? – – 
 46 (D, V) 61 74 74 
Ventrolateral prefrontal cortex 
 12L 82 80 83 
 12M 55 – – 57 
 12O 69 – – 56 
 45 – – – – 65 
Orbitofrontal cortex 
 11 71 71 F? 43 L? 
 13 (L, M) 72 F? 70 25 B? 
 Orbital insula 18 B? – – – – 
Medial cortex 
 23 (a–c) 77 87 61 
 23V – – – – 57 L? 
 24 (a, b) 47 92 F? – – 
 29a–d 84 68 – – 
 30 67 87 – – 
 32 40 – – – – 
 ProSt 68 F? – – – – 
Premotor cortex 
 6M 81 – – – – 
 6DC 55 89 F? 45 
 6DR 67 90 51 
 6V – – – – 67 
 8C – – – – 67 
Temporal association cortex 
 Parabelt, TPt 63 L? 85 – – 
 STP, PGa + IPa 68 63 L? 82 
 TE1–TE3 81 F? – – 88 
 Parahippocampal 40 L? – – 19 B? 
Posterior parietal cortex 
 AIP – – – – 68 
 LIP – – – – 57 
 MIP – – – – 42 
 VIP – – – – 61 L? 
 PE, PEC – – 73 F? 75 
 PF – – 80 F? 95 
 PFG 40 L? – – 83 
 PG – – 79 F? 65 
 Opt – – – – 67 
 PGM – – 79 F? 59 L? 
 31 – – 96 91 F? 
Visual cortex 
 V2 – – – – 92 
 VLP(V3) – – – – 79 
 VLA(V4) – – – – 78 
 MT – – – – 72 
 MTC – – – – 78 
 MST – – – – 77 
 FST – – – – 74 
 DM(V6) – – – – 68 
 DA(V3A) – – – – 62 
 DI – – – – 67 
 V6A – – – – 95 F? 
 19M – – – – 67 
 TEO – – – – 92 F? 

‘?’ Indicates uncertain classification due to small sample size (<50 neurons).

Results

Seven neuroanatomical tracer injections were examined (Table 1). Two injections were placed within each of the histologically identified areas 8aD and 8b, and 3 in area 8aV. Only 1 injection partially infiltrated an adjacent area (the 8aV injection in case CJ94, which slightly crossed the border into the adjacent area 45).

Cytoarchitectonic Identification of the Subdivisions of Area 8

The 3 areas that form the BA8 complex in the marmoset have distinct patterns of staining for Nissl substance and myelin (Fig. 3), and, to a lesser extent, cytochrome oxidase. Given that the architectural characteristics of these areas have been described and illustrated in detail elsewhere (Burman et al. 2006; Roberts et al. 2007; Burman and Rosa 2009a,b), only the main distinguishing features will be highlighted here. As reported originally by Walker (1940), area 8b shows a thinner and more diffuse layer 4, and a more homogeneous layer 5, in comparison with the other subdivisions. Areas 8aD and 8aV both exhibit a more sharply defined layer 4, which is particularly thick in 8aV, and both show resolvable layers 5a and 5b. Area 8aV is further characterized by the presence of large, scattered pyramidal cells in the upper part of layer 5, which are not present in the ventrally adjacent area 45; this distinction provides a reliable criterion for defining the border between these areas (Burman et al. 2006).

Figure 3.

Histological characteristics of areas 8b, 8aD, and 8aV in the marmoset. (Top) Section stained for myelin, using the Gallyas technique. (Bottom) Section stained for Nissl substance, using cresyl violet. The approximate locations of the boundaries are indicated by the arrowheads. The insert (upper right) indicates the level of these sections (approximately A + 15.5 mm). Scale bar (bottom left) = 500 µm.

Figure 3.

Histological characteristics of areas 8b, 8aD, and 8aV in the marmoset. (Top) Section stained for myelin, using the Gallyas technique. (Bottom) Section stained for Nissl substance, using cresyl violet. The approximate locations of the boundaries are indicated by the arrowheads. The insert (upper right) indicates the level of these sections (approximately A + 15.5 mm). Scale bar (bottom left) = 500 µm.

Myelin stains reveal area 8aV as one of the most densely myelinated regions in the prefrontal cortex (Fig. 3; see also Bock et al. 2009). According to this criterion, area 8aV is distinct from area 8aD (a less myelinated region, in which clear inner and outer bands of Baillarger can be distinguished), but not as clearly separable from area 45. Whereas the caudal borders of the areas encompassed in the BA8 complex with premotor areas are readily identifiable based on both cyto- and myeloarchitecture (Burman et al. 2006), the rostral borders with other prefrontal areas, particularly area 46, are not as clearly resolved in the marmoset, using coronal sections. This uncertainty is somewhat alleviated by the use of the cytochrome oxidase stain, which reveals areas 9 and 46 as less densely stained than any subdivision of area 8 (data not shown; see Fig. 9 in Burman et al. 2006). The characteristics of areas 8aV, 8aD, and 8b observed in our material are consistent with previous descriptions of this region in macaques (Petrides and Pandya 1999; see Burman et al. 2006 for comparative data).

A recent stereotaxic atlas of the marmoset recognizes an additional putative subdivision of the BA8 complex, which is referred to as area 8C (8 caudal; Paxinos et al. 2012). This subdivision has been portrayed as a thin wedge of cortex inserted between the dorsal and ventral premotor complexes (Fig. 2). In a previous study (Burman et al. 2006), this region was considered to be part of the caudal dorsal premotor area (area 6DC), and examination of the present tissue confirmed that it shares its key architectural features with the dorsal premotor areas. Most importantly, the area 8C territory shows a poorly developed layer 4 (Burman et al. 2012), a characteristic that makes it quite distinct from the areas that we explored here. This putative new subdivision did not receive tracer injections in the present study, but was considered separately from the dorsal and ventral premotor areas for the purpose of reporting the location of labeled neurons.

Main Features of the Distribution of Labeled Neurons Across Cases

In all cases, a relatively large fraction of the labeled neurons represented intrinsic connections, within the same area that contained the injection site. The percentage of neurons forming intrinsic connections is notoriously difficult to quantify, due to factors such as damage at the injection site, and the likely passive uptake of the tracer by diffusion. In our cases, the percentage of intrinsic connections ranged between 33.0% and 49.2% of the total label. These need to be seen as minimum estimates, reflecting what was likely a very conservative criterion, and indeed they are lower than figures revealed by analyses that were specifically designed to clarify the relative weight of intrinsic versus extrinsic connectivity (Markov et al. 2011). All other quantitative analyses, presented in the subsequent sections of this paper, refer to extrinsic connections.

Figure 4 shows a comparison of the complete population of labeled corticocortical neurons following 4 tracer injections, in the format of 2D maps of the marmoset cerebral cortex. These maps represent the results of 1 injection in each of areas 8b, 8aD, and 8aV (Fig. 4AC), and 1 injection in area 8aV that included the border zone with area 45 (Fig. 4D). The locations of these neurons with respect to the boundaries of cortical areas are discussed in detail below, and are illustrated in subsequent figures (Figs 6–10). The percentages of neurons labeled in each cortical area are presented in more detail in Table 3.

Figure 4.

Summary maps showing the distribution of labeled neurons following 4 injections of tracers in subdivisions of BA8. Each panel illustrates a 2-dimensional reconstruction prepared using CARET (Van Essen et al. 2001), using the same conventions as in Figure 2, including orientation (rostral to the right, ventral downwards) and the locations of the discontinuities used to reduce distortions. The gray shading represents curvature: Convex (outward-projecting) surfaces such as dorsal midline and the lips of the lateral fissure (lf) appear lighter than the gray background, whereas concave (inward-projecting) surfaces such as the banks of the lateral fissure appear darker than the background. Colored points represent individual neurons labeled with DY (yellow), FR (red), and FE (green), and the centers of the injection sites are indicated by black circles. For orientation, the locations of several areas containing labeled neurons are indicated (compare with the full reconstruction shown in Fig. 2). Other abbreviations: cal, calcarine sulcus; cc, corpus callosum; ips, intraparietal sulcus; sts, superior temporal sulcus. Scale bar = 5 mm.

Figure 4.

Summary maps showing the distribution of labeled neurons following 4 injections of tracers in subdivisions of BA8. Each panel illustrates a 2-dimensional reconstruction prepared using CARET (Van Essen et al. 2001), using the same conventions as in Figure 2, including orientation (rostral to the right, ventral downwards) and the locations of the discontinuities used to reduce distortions. The gray shading represents curvature: Convex (outward-projecting) surfaces such as dorsal midline and the lips of the lateral fissure (lf) appear lighter than the gray background, whereas concave (inward-projecting) surfaces such as the banks of the lateral fissure appear darker than the background. Colored points represent individual neurons labeled with DY (yellow), FR (red), and FE (green), and the centers of the injection sites are indicated by black circles. For orientation, the locations of several areas containing labeled neurons are indicated (compare with the full reconstruction shown in Fig. 2). Other abbreviations: cal, calcarine sulcus; cc, corpus callosum; ips, intraparietal sulcus; sts, superior temporal sulcus. Scale bar = 5 mm.

Figure 6.

(AO) Coronal sections illustrating the locations of labeled neurons (yellow–green points) relative to architectural boundaries of cortical areas, following a tracer injection in area 8b (case CJ83-DY). The injection site is indicated in black in (E). The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. Abbreviations for subcortical labeled neurons (according to Paxinos et al. 2012): AM, anteromedial nucleus; APT/PLi, anterior pretectal nucleus and posterior limitans nucleus; AV, anteroventral nucleus; Cl, claustrum; CL, central lateral nucleus; CM, central medal nucleus; IAM, interanteromedial nucleus; MD, mediodorsal nucleus; MDC, caudal mediodorsal nucleus; MDL, lateral mediodorsal nucleus; MDM, medial mediodorsal nucleus; NBM, nucleus Basalis of Meynert; RT, reticular nucleus; ZIR, rostral zona incerta. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to O) = 2 mm.

Figure 6.

(AO) Coronal sections illustrating the locations of labeled neurons (yellow–green points) relative to architectural boundaries of cortical areas, following a tracer injection in area 8b (case CJ83-DY). The injection site is indicated in black in (E). The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. Abbreviations for subcortical labeled neurons (according to Paxinos et al. 2012): AM, anteromedial nucleus; APT/PLi, anterior pretectal nucleus and posterior limitans nucleus; AV, anteroventral nucleus; Cl, claustrum; CL, central lateral nucleus; CM, central medal nucleus; IAM, interanteromedial nucleus; MD, mediodorsal nucleus; MDC, caudal mediodorsal nucleus; MDL, lateral mediodorsal nucleus; MDM, medial mediodorsal nucleus; NBM, nucleus Basalis of Meynert; RT, reticular nucleus; ZIR, rostral zona incerta. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to O) = 2 mm.

Comparison of the flat maps yields several significant differences in the global pattern of connectivity between cytoarchitectural subdivisions of the BA8 complex, in agreement with the notion that each of these is best conceptualized as a distinct cortical area. For instance, although the posterior cingulate/retrosplenial sector projected to all subdivisions of area 8, there was clear segregation of these projections. Neurons projecting to area 8b (Fig. 4A) were located ventrally in the midline cortex (i.e., toward the top of the maps), chiefly in subdivisions of supracallosal areas 29 and 30, with some inclusion of area 23a. In comparison, neurons projecting to area 8aD (Fig. 4B) concentrated more dorsally, being located predominantly in subdivisions of area 23, and included to a larger extent medial parietal areas 31 and PGM, whereas projections to area 8aV were sparser overall, and originated primarily from the latter areas (Fig. 4C). Another example of a prominent difference in connectivity was in the pattern of projections from the lateral and inferior temporal sector (lit). In this case, the projection to area 8b formed an elongated band along the dorsal portion of this sector, which was centered on the superior temporal polysensory (STP) area. In comparison, projections to area 8aD were much sparser (Fig. 4B), originating from areas located more caudally (parabelt and TPt). Projections to area 8aV, when present (Fig. 4D), were concentrated more ventrally, in putative polysensory (IPa/PGa) and visual (TE3/TEO) areas.

The distributions of labeled neurons across the main cortical sectors are compared in Figure 5, which depicts cell counts expressed as a percentage of the total extrinsic cortical label. The strong bias for connections with other areas located within the prefrontal cortices is emphasized by this format of presentation. There was a clear gradient of connectivity within the frontal lobe, with areas 8b and 8aD receiving projections primarily from the dorsolateral prefrontal areas, and 8aV primarily from ventrolateral prefrontal areas (vlp). Area 8b was distinctive in receiving relatively dense projections from the medial prefrontal (mpc) and anterior cingulate (acc) cortices, and by the lack of connections with the posterior parietal (ppc) and visual (vis) cortices. Among the 3 subdivisions of the BA8 complex, area 8aD received the densest projections from the orbitofrontal (ofc), auditory (aud), and posterior cingulate/retrosplenial (pcr) cortices. Finally, in addition to the marked input from ventrolateral prefrontal areas, the hallmark of injections in area 8aV was the presence of numerous projections from various visual areas (vis), the identity of which varied according to the exact location of the injection sites (see below). Neurons in the premotor sector (prm) formed substantial projections to all 3 areas, although, as detailed below, there was some variation in the exact complement of areas forming these projections.

Figure 5.

Percentages of neurons labeled in different cortical sectors, following injections of retrograde tracers in areas 8b (top), 8aD (middle), and 8aV (bottom). Black, white, or gray bars label the data from different cases, and only extrinsic connections are shown. The abbreviations of the cortical sectors are: dlp, dorsolateral prefrontal cortex; vlp, ventrolateral prefrontal cortex; ofc, orbitofrontal cortex; mpc, medial prefrontal cortex; prm, premotor/motor cortex; acc, anterior cingulate cortex; ssc, somatosensory cortex; ins, insular cortex; aud, auditory cortex; lit, lateral/inferior temporal cortex; vtc, ventral temporal cortex; ppc, posterior parietal cortex; pcr, posterior cingulate/retrosplenial cortex; vis, visual cortex. Because no tracer-filled cells were observed in the olfactory cortex in any case, this sector is not represented in the graphs. See Figure 2 for the areas included in each sector.

Figure 5.

Percentages of neurons labeled in different cortical sectors, following injections of retrograde tracers in areas 8b (top), 8aD (middle), and 8aV (bottom). Black, white, or gray bars label the data from different cases, and only extrinsic connections are shown. The abbreviations of the cortical sectors are: dlp, dorsolateral prefrontal cortex; vlp, ventrolateral prefrontal cortex; ofc, orbitofrontal cortex; mpc, medial prefrontal cortex; prm, premotor/motor cortex; acc, anterior cingulate cortex; ssc, somatosensory cortex; ins, insular cortex; aud, auditory cortex; lit, lateral/inferior temporal cortex; vtc, ventral temporal cortex; ppc, posterior parietal cortex; pcr, posterior cingulate/retrosplenial cortex; vis, visual cortex. Because no tracer-filled cells were observed in the olfactory cortex in any case, this sector is not represented in the graphs. See Figure 2 for the areas included in each sector.

The use of non-parametric statistical techniques confirmed the significance of the differences between areas. First, analysis of the concordance of tracer distribution patterns across areas yielded no significant association (Kendall's W = 0.55, Friedman's χ2= 21.45, df = 13, P > 0.05, not significant (n.s.)). Second, individual pairwise comparison across areas using the Spearman rank correlation coefficient did not yield any significant correlations between subdivisions, although the RS values suggested that the degree of association between 8aD and either of the other areas was greater than the association between 8b and 8aV (8b vs. 8aD, RS = 0.506, T = 2.03, 0.1 > P > 0.05; 8b vs. 8aV, RS = 0.049, T = 0.172, 1.0 > P > 0.5; 8aD vs. 8aV, RS = 0.519, T = 2.10, 0.1 > P > 0.05; all df = 12, all n.s.). The latter inference is justified based on the fact that the degree of difference between contributors to the Kendall W statistic is directly related to the magnitude of the difference between the observed P-value and the alpha level, in “a posteriori” tests (Legendre 2005). Finally, as detailed below, we found that injections into the same target area always showed very good agreement in the pattern of distribution across sectors (i.e., highly significant RS values).

Distribution of Tracer in Different Cortical Areas Following Injections in Area 8b

Injections were placed into area 8b in cases CJ83-DY and CJ74-FB. The complete pattern of labeled neurons in case CJ83-DY is shown in the flat map presentation in Figure 4A. A more detailed view of the pattern of label obtained in this case, including the relationship of labeled neurons to architectural boundaries, is shown in Figure 6.

In the dorsolateral prefrontal cortex, area 8b showed dense connectivity with areas 8aD, 9, 10, and 46D (Fig. 6BE). Connections with areas 46V and 8aV were much sparser in comparison (Fig. 6AE). The pattern of frontal connections was distinct from those observed after injections in areas 8aD and 8aV (described below) in that there was significant label in the medial prefrontal cortex (area 32, Fig. 6CE), which extended into the anterior cingulate areas (areas 24a–c; Fig. 6FH; see also Table 3). Labeled neurons in the ventrolateral prefrontal cortex were distributed almost equally between the lateral, medial, and orbital subdivisions of area 12 (Fig. 6CG; Table 3), but also extended more medially and caudally to include subdivisions of orbitofrontal areas 11 and 13, and the orbital insular complex (OPAl and OPro; Fig. 6E,G,H). Further caudally, dense concentrations of labeled neurons were detected in the dorsal rostral premotor area (6DR), with fewer neurons being located in the dorsal caudal premotor area (6DC; Burman et al. 2008; Fig. 6FH) and the medial premotor area (6M).

Longer-ranging connections were observed from the temporal lobe. These originated primarily from the STP (Fig. 6JL) and the putative polysensory cortex along the fundus of superior temporal sulcus (PGa/IPa; see Table 3). However, sparser label was observed to extend into adjacent areas (Fig. 6IL), including the caudal parabelt, the rostral superior temporal area, and inferior temporal visual areas (TE1–TE3). In addition, a few neurons were found ventrally, in the medial part of the temporal lobe (primarily in areas TH and TL). Labeled neurons in the posterior parietal cortex were very rare (Fig. 5 and Table 3). They were observed in medial parietal areas PGM and 31, and in ventral parietal area PFG (Fig. 6M). Finally, substantial projections originated from the supracallosal and retrosplenial cortices (subdivisions of areas 29 and 30; Fig. 6JO), with some invasion of the ventral sector of the posterior cingulate cortex (areas 23a and 23V).

These major findings were reflected in the second case, CJ74-FB, which had a much smaller, and slightly more caudal injection in area 8b (Table 1). The main notable differences observed in this case, in comparison with the pattern described above, were the absence of labeled neurons in the orbital insular, caudal premotor, and ventral parietal cortices, and the presence of substantial label in more caudal parts of the retrosplenial cortex, including a clear projection from area prostriata, in the dorsal bank of the calcarine sulcus (Fig. 7). Nevertheless, the distribution of labeled neurons across different cortical sectors was highly correlated (Spearman's rank correlation; RS = 0.95, P < 0.001).

Figure 7.

(AC) Coronal sections illustrating the locations of labeled neurons (black squares) in the retrosplenial and calcarine cortices following a tracer injection in area 8b (case CJ74-FB). The approximate A–P levels are shown in italicized numbers to the right of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to A) = 1 mm.

Figure 7.

(AC) Coronal sections illustrating the locations of labeled neurons (black squares) in the retrosplenial and calcarine cortices following a tracer injection in area 8b (case CJ74-FB). The approximate A–P levels are shown in italicized numbers to the right of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to A) = 1 mm.

Distribution of Tracer in Different Cortical Areas Following Injections in Area 8aD

Injections were placed into 8aD in cases CJ108-FR and CJ70-FR. The pattern of labeled neurons for case CJ108-FR is shown in detail in Figure 8. In the frontal lobe, labeled neurons were numerous in areas 8b, 9, and 46, but were also present in areas 8aV and 10, albeit in smaller numbers (Fig. 8AE, Table 3). In the premotor cortex, relatively dense label was observed in area 6DR (Fig. 8E), with smaller numbers of neurons also present in adjacent areas. In addition, there was moderate to dense label in the ventrolateral prefrontal cortex, particularly in area 12L (Fig. 8B,C), and in the lateral parts of orbitofrontal areas 11 and 13 (e.g., Fig. 8D; see also Table 3). In contrast with injections in area 8b, the medial prefrontal cortex was devoid of label, and many fewer labeled neurons were observed in the anterior cingulate (Table 3).

Figure 8.

(AJ): Coronal sections illustrating the locations of labeled neurons (red circles) relative to architectural boundaries of cortical areas, following a tracer injection in area 8aD (case CJ108-FR). The injection site (formed by 2 parallel syringe tracks, see Fig. 1) is indicated in black in D. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (below J) = 2 mm.

Figure 8.

(AJ): Coronal sections illustrating the locations of labeled neurons (red circles) relative to architectural boundaries of cortical areas, following a tracer injection in area 8aD (case CJ108-FR). The injection site (formed by 2 parallel syringe tracks, see Fig. 1) is indicated in black in D. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (below J) = 2 mm.

Posterior cingulate projections to area 8aD were very robust, including input from areas 23a–c and 30, as well as a sparser input from area 29 (Fig. 8FH). Other patches of sparse label along the medial surface were located in the medial parietal area PGM, area 31, and visual area 19M (Fig. 8J). In addition, area 8aD received input from the posterior parietal sector, which included projections from ventral parietal areas PG and PF (e.g., Fig. 8H), dorsal parietal area PE, and the lateral and ventral intraparietal areas LIP and VIP, e.g., Fig. 8H). In both cases of injections in 8aD, only scattered labeled neurons were observed in the temporal lobe. These neurons were located in high-order auditory association cortices, primarily in the parabelt and TPt (e.g., Fig. 8G), and in the medial superior temporal visual area (MST; Table 3). The data from a second animal (CJ70-FR) were highly concordant with the above description in terms of quantitative distribution across different cortical sectors (RS = 0.84, P < 0.001). In this case, however, we observed small patches of labeled neurons along the polysensory cortex of the lateral temporal lobe (areas STP and PGa/IPa; Table 3), which were absent from CJ108-FR.

Distribution of Tracer in Different Cortical Areas Following Injections in Area 8aV

Area 8aV in the marmoset encompasses the main frontal territory from which eye movements can be evoked (Blum et al. 1982; Burman et al. 2006, 2008). Of the 3 injections aimed at area 8aV, 2 were entirely restricted to the borders of this area (CJ75-DY and CJ108-FE), whereas 1 slightly invaded adjacent area 45 (CJ94-DY). Despite the differences in location, the distribution of labeled neurons was highly concordant across all 3 cases (Kendall's W = 0.86; Friedman's χ2= 33.7, df = 13, P < 0.01). The rank correlation between projections from different cortical sectors to the 2 injections restricted to area 8aV was also very high (RS = 0.88, P < 0.001).

The distribution of labeled neurons in case CJ108-FE is illustrated in Figure 9. With only minor differences, noted below, this description also applies to CJ75-DY, even though these injections resulted in a very different number of labeled neurons (Tables 1 and 3). As specified below, the main distinction between these cases was in the location of label relative to the boundaries of extrastriate visual areas, probably reflecting the topography of representation of central versus peripheral visual space. Thus, in Figure 10, we illustrate sections from the caudal part of the brain of CJ-75DY, to better document these differences.

Figure 9.

(AM) Coronal sections illustrating the locations of labeled neurons (green circles) relative to architectural boundaries of cortical areas, following a tracer injection in area 8aV (case CJ108-FE). The injection site is indicated in black in B and C. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to M) = 2 mm.

Figure 9.

(AM) Coronal sections illustrating the locations of labeled neurons (green circles) relative to architectural boundaries of cortical areas, following a tracer injection in area 8aV (case CJ108-FE). The injection site is indicated in black in B and C. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to M) = 2 mm.

Figure 10.

(AF) Coronal sections illustrating the locations of labeled neurons (yellow–green circles) relative to architectural boundaries of cortical areas, following a tracer injection in the area 8aV (case CJ75-DY). The injection site is indicated in black in the A. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to F) = 2 mm.

Figure 10.

(AF) Coronal sections illustrating the locations of labeled neurons (yellow–green circles) relative to architectural boundaries of cortical areas, following a tracer injection in the area 8aV (case CJ75-DY). The injection site is indicated in black in the A. The gray lines indicate the boundaries of areas containing labeled neurons, with the approximate stereotaxic A–P levels shown in italicized numbers at the bottom left of each section. The insert indicates the section levels in a lateral view of the right hemisphere. Scale bar (adjacent to F) = 2 mm.

In the frontal lobe, area 8aV received numerous projections from the ventrolateral prefrontal cortex (primarily areas 12L and 45, but also, to a lesser extent, areas 12M and 12O) and from dorsolateral prefrontal area 46V (Figs 9AE and 10A). There was no label in area 46D, and relatively few connections were detected with areas 8b and 8aD; the former projection, in particular, was very sparse (Figs 9B,C and 10A). The medial prefrontal cortex was not labeled, with the exception of a few isolated neurons observed only in CJ75-DY (e.g., Fig. 10A), whereas the orbitofrontal cortex contained very sparse label, primarily in area 13L (Figs 9C,D and 10A). Sparse to moderate projections were observed from premotor areas, which originated primarily in areas 6DR and 6V (Fig. 9E,F). However, smaller numbers of neurons were also found in area 6DC in each case. Area 8aV was distinctive among the subdivisons of BA8 in showing dense connections with area 8C, the new subdivision of premotor cortex proposed by Paxinos et al. (2012). This area, located between the dorsal and ventral premotor cortices (Fig. 9E,F), is known to have projections to dorsal stream extrastriate areas (Burman et al. 2006; note that area 8C was referred to, at that time, as a more densely myelinated subdivision of area 6DC).

All injections in area 8aV revealed marked connections with the posterior parietal cortex (Fig. 4C,D). Projections originated from the dorsal parietal areas, including: anterior intraparietal area (AIP), LIP, medial intraparietal area (MIP), VIP, PE, and PEc (Figs 9HJ and 10B,C), as well as from ventral parietal areas, including: Opt, PG, PFG, and PF (Figs 9GI and 10B,C). Label in area LIP was denser in cases CJ75-DY and CJ94-DY than in CJ108-FE. On the medial surface of the caudal parietal lobe, labeled neurons were observed in areas PGM and 31 (Figs 9IK and 10D,E), in a pattern that was very consistent across cases. Relatively few projecting neurons were observed in the posterior cingulate or retrosplenial areass.

The main difference between the patterns of connections revealed by injections in area 8aV and those in other subdivisions of BA8 was the presence of substantial label in visual areas. The assignment of label to specific visual areas was somewhat different in the 2 cases of injections restricted to area 8aV, most likely due to the injection sites involving small and large saccade sectors of the frontal eye field (Schall et al. 1995; Stanton et al. 1995). In case CJ108 (Figs 4C and 9), the injection site was located near the anterior border of area 8aV. This resulted in a concentration of label in regions of extrastriate cortex associated with far peripheral vision, particularly in areas that are preferentially connected with the dorsal (occipitoparietal) stream (Rosa et al. 2009). In contrast, the injection in case CJ75-DY was in the caudal part of area 8aV, and led to substantial label in the representations of central and near-peripheral vision in extrastriate areas (Rosa and Elston 1998; Rosa and Tweedale 2000; Rosa et al. 2005). In both cases, there were distinct patches of labeled neurons in the middle temporal area (MT; Figs 9I and 10B,C), which extended into adjacent sectors of the middle temporal crescent (corresponding to area V4T of Old World monkeys), the MST area, and the fundus of superior temporal area (FST; see Figs 9IK and 10BE). Other dorsal stream areas that contained distinct patches of labeled neurons included the dorsoanterior area (DA/V3A; Figs 9L and 10DF), visual area 6A (V6A; Fig. 9J), and medial area 19 (19M; Figs 9K,L and 10E,F). Label in the second (V2), ventrolateral posterior (V3/VLP), DA/V3A, ventrolateral anterior (V4/VLA), and dorsomedial (V6/DM) visual areas was denser in the case with the central injection (CJ75-DY). Conversely, in case CJ108-FE, we observed relatively stronger label in MST and V6A.

With the exception of the complex of motion-sensitive areas around MT (noted above), and a few isolated neurons in parahippocampal area TH, little retrograde label was observed in the temporal lobe in case CJ108-FE. Projections from the dorsal portion of inferior temporal areas TE3 (ITd) and TEO (ITc) were more prominent in case CJ75-DY (Fig. 10BE). The results of injections in area 8aV were distinctive in that the main projection from the polysensory temporal cortex originated in areas PGa/IPa, rather than in STP (Table 3). Projections from lateral and inferior temporal areas were also prominent in the case in which the injection invaded area 45 (CJ94-DY; Fig. 4D and Table 3). The other main differences between this case and those with injections restricted to area 8aV were the presence of projections originating in area 9 and in the anterior cingulate.

Laminar Patterns of Projections

Similar to our previous observations regarding the connections of prefrontal area 10 (Burman, Reser, Yu, et al. 2011), we found that many of the projections to the 3 subdivisions of the BA8 complex showed relatively balanced laminar distribution across supragranular and infragranular layers, thus qualifying as “lateral” or “intermediate” projections according to commonly used criteria (Maunsell and Van Essen 1983; Grant and Hilgetag 2005). Most of the projections from nearby areas of the dorsolateral prefrontal cortex conformed to this pattern. In the frontal lobe, projections that showed marked supragranular laminar biases (feedforward-like) were most commonly found to originate from ventrolateral, orbital, and medial areas. In addition, the majority of connections originating outside the frontal lobe had feedforward characteristics. Perhaps surprisingly, none of the main projections to any subdivision of BA8 exhibited a strong infragranular bias (%SLN ≤ 33), which would suggest a feedback connection (Table 4), although some of the sparser projections (e.g., those from area 13 and the parahippocampal areas to area 8aV, and that from the orbital insular areas to area 8b) were compatible with this pattern.

Among the areas in which we observed at least 50 labeled neurons following injections in area 8b, 9 exhibited roughly balanced supra- and infragranular label, suggesting lateral connectivity (Table 4). There was, however, a supragranular bias (%SLN ≥ 67) in the projections from prefrontal areas 11, 12L and 12O, premotor areas 6DR and 6M, posterior cingulate/retrosplenial areas 23, 29, and 30, and temporal areas STP and PGa/IPa, suggesting feedforward projections. Among areas with sizeable projections to 8aV, a clear supragranular bias was observed in the projections from frontal areas 8b, 12L, 46, 6V, and 8C, temporal areas TE3 and PGa/IPa, posterior parietal areas AIP, PE, PEC, PF, PFG, and OPt, and the vast majority of the extrastriate visual areas (Table 4; Supplementary Fig. S1). The numbers of labeled neurons following from both injections in area 8aD were relatively small, in general allowing fewer firm conclusions about laminar organization. Nevertheless, some of the projections to area 8aD exhibited a marked supragranular laminar bias, including those from areas 8aV, 12L, 13, 46, premotor area 6DR, TPt, anterior and posterior cingulate areas, auditory association areas, and medial parietal area 31.

In 6-layered cortices, the vast majority of supragranular projections originated from layer 3; the very few putative layer 2 neurons were located so close to the boundary with layer 3 that an unambiguous assignment based on a comparison between adjacent sections was difficult. Projections to infragranular layers of BA8 originated predominantly in layer 5, particularly in the case of long-range connections from the temporal and parietal lobes. Projections that appeared to arise in layer 6 most commonly originated from other areas in the frontal cortex; even in this case, however, the number of labeled neurons in this layer was smaller than in layer 5 (Barbas 1986).

Discussion

Using injections of fluorescent tracers, we characterized the afferent connections of 3 subdivisions (8b, 8aD, and 8aV) of the caudal prefrontal cortex in the marmoset monkey. Our data, summarized in Figure 11, demonstrate that BA8 is better described as a complex, formed by functionally distinct areas, as suggested by earlier cytoarchitectural studies of the corresponding region in the baboon, macaque, human, and marmoset brains (Watanabe-Sawaguchi et al. 1991; Petrides and Pandya 1999; Burman et al. 2006). Whereas a degree of variability was observed between replicate injections within the same area, these differences were small in comparison with those revealed by comparisons between areas (Fig. 11). Thus, although not completely excluding the possibility of finer subdivisions, our data support the view that these cytoarchitectural areas are likely to represent the prime functional subdivisions of the BA8 complex.

Figure 11.

Summary of the afferent connections of the 3 areas comprising the BA8 complex in the marmoset. (Top) Medial, lateral, and ventral views of the brain, showing the cortical areas that send the principal projections to areas 8b, 8aD, and 8aV. The areas are coded according to the same color scale used in the bottom diagram, but only projections formed by >0.5% of the labeled neurons are represented. The assigned colors reflect the densest value of the 2 results for a projection from a given area (the results of case CJ94-DY, with an injection that invaded area 45, were not considered for this purpose). (Bottom) Results from individual cases, color-coded according to the percentage of labeled neurons, observed in the different areas (see scale on the far right). This format highlights the similarities between observations in 2 cases of injections in the same area, as well as differences between injections in the different areas (for abbreviations, see Tables 2 and 3). For ease of comparison, the boxes along each row (each corresponding to 1 area) are arranged in the same sequence as the areas are listed in Table 3.

Figure 11.

Summary of the afferent connections of the 3 areas comprising the BA8 complex in the marmoset. (Top) Medial, lateral, and ventral views of the brain, showing the cortical areas that send the principal projections to areas 8b, 8aD, and 8aV. The areas are coded according to the same color scale used in the bottom diagram, but only projections formed by >0.5% of the labeled neurons are represented. The assigned colors reflect the densest value of the 2 results for a projection from a given area (the results of case CJ94-DY, with an injection that invaded area 45, were not considered for this purpose). (Bottom) Results from individual cases, color-coded according to the percentage of labeled neurons, observed in the different areas (see scale on the far right). This format highlights the similarities between observations in 2 cases of injections in the same area, as well as differences between injections in the different areas (for abbreviations, see Tables 2 and 3). For ease of comparison, the boxes along each row (each corresponding to 1 area) are arranged in the same sequence as the areas are listed in Table 3.

In the case of injections in different parts of area 8aV, differences in connections could be related to the well-established visual topography of extrastriate areas. The small differences observed between injections within areas 8aD and 8b are harder to interpret based on current knowledge, but it is plausible that they also reflect variations related to an unknown functional gradient or topography within these areas. These variations are not specific to the present data: Studies in visual and visuomotor cortices have demonstrated similar or, in some cases, even more marked gradients of connections between parts of areas that are well defined in terms of cyto- and myeloarchitecture, receptive field properties, and/or topographic representation (Sousa et al. 1991; Palmer and Rosa 2006b; Ungerleider et al. 2008; see Gamberini et al. 2011 for a general discussion).

One possible limitation of anatomical tracing analyses similar to those we conducted is linked to the existence of sparse connections, represented by only a few, isolated labeled neurons. Analysis of Figure 11 and Table 3 reveals that connections formed by 0.1% or fewer of the extrinsic labeled neurons corresponded to 27.8% of the interareal pathways detected across the 7 cases (88 of the 317 connections reported). Considering that only 1 in 5 sections was analyzed, the risk of false negatives is real, and this factor is likely to contribute to the observed variability between injections in the same area. The risk of false negatives is probably exacerbated in studies of the marmoset, where the small volume of the cortical areas demands the use of smaller injection sites in comparison with studies in macaques, which in turn leads to relatively small numbers of labeled neurons. Nevertheless, it was reassuring to observe that analyses based on the percentages of labeled neurons revealed highly consistent results, as confirmed by statistical analyses. Finally, it must be recognized that the number of labeled neurons is only a very indirect indication of the functional strength of a connection (i.e., the effect it is likely to have on the post-synaptic neurons in the target area); an appropriate functional assessment of the importance of an anatomical pathway can only be rigorously evaluated by other techniques, such as intracellular recordings.

Comparisons of connections of cortical areas in primates are further complicated by the fact that they are usually based on a relatively small number of cases across different species, and by what seem to be genuine species differences, which are likely to be linked to evolutionary scaling rules derived from the relationship between brain size (i.e., number of neurons) and optimal network configuration (Palmer and Rosa 2006a; Burman, Reser, Yu, et al. 2011). Keeping these factors in mind, in the following paragraphs we will compare our results with those described for the caudal prefrontal cortex of other species, with particular focus on macaques, which remain the most extensively characterized species of non-human primate in this respect.

Connections of Area 8b

Much of what is known about the connectivity of area 8b comes from studies of tracer injections in other parts of the brain, which yielded labeled neurons and terminals in this area. The results of fluorescent tracer injections in area 8b of a macaque monkey (Macaca mulatta), described by Petrides and Pandya (1999), revealed key similarities with our data. In the frontal cortex, there is high concordance between species, including dense connections with area 9, connections with area 46 that were concentrated in its dorsal subdivision, and sparse inputs from the medial part of area 10 and orbitofrontal cortex. In addition, results in both species agree with respect to the existence of a substantial projection from the dorsal premotor cortex, particularly area 6DR. The results of Petrides and Pandya also highlight the fact that, among all subdivisions of the BA8 complex, area 8b has the densest connections with medial prefrontal and anterior cingulate areas. In addition, our results converge with those of Watanabe-Sawaguchi et al. (1991) in the baboon, in the observation that area 8b has denser connections with the dorsal part of area 46 and with area 8aD, relative to ventral areas 46 and 8aV.

Our observations on the longer-range projections to area 8b are also in general agreement with those obtained in the macaque, in highlighting the presence of labeled neurons in the polysensory sector of the temporal lobe (primarily area STP), in ventral posterior parietal areas, and in the ventral part of the posterior midline cortex (areas 29, 30, and 23). Sparse label was also observed in the parahippocampal cortex, including area TH, of both species. However, the correspondence is not exact. For example, in macaques the posterior cingulate/supracallosal label was reported to include medial parietal areas 31 and PGM to a larger extent than suggested by our data. Conversely, in marmosets the projection from superior temporal cortex appears to be more extensive than was apparent in the macaque case illustrated by Petrides and Pandya (1999), in that we found some labeled neurons that were clearly located outside the boundaries of area STP (cytoarchitectural field TPO), both ventrally (PGa/IPa, TE3) and dorsally (parabelt and rostral superior temporal cortex).

The projections from auditory areas raise the question of whether our injection sites in area 8b may have invaded area 8aD, which according to Petrides and Pandya (1999) receives the bulk of the auditory connections among the subdivisions of BA8. However, label in area 8b has been reported following an injection in the lateral auditory cortex of the macaque (Romanski, Tian, et al. 1999), and auditory-driven activity has been recorded in this area (Bon and Lucchetti 2006; Lucchetti et al. 2008). In addition, the pattern of connections observed after our injections is in most other ways highly consistent with that observed following injections in macaque area 8b; most tellingly, we never observed label in parietal areas that are known to be connected to 8aD, including PE, AIP, and VIP (Petrides and Pandya 1999). Clear parietal label would also be expected from invasion of area 6DR, which lies caudal to area 8b. When combined with the clear difference in cytoarchitecture between areas 8aD and 8b, these arguments make it highly unlikely that our area 8b injections invaded adjacent areas, or that the current assessment of areal homologies is wrong. We note that both of our injections were located quite medially within area 8b, whereas those reported by Petrides and Pandya (1999) in the macaque were located in the lateral part of this area. In general, though, we believe that the similarities between species are very significant, particularly considering over 40 million years of divergent evolutionary history (Chatterjee et al. 2009) and a 12-fold difference in brain volume (Stephan et al. 1981). Together with the similarity in cytoarchitecture (Burman et al. 2006), these findings make a strong case for homology of area 8b across simian primates.

Connections of Area 8aD

Petrides and Pandya (1994, 1999) proposed the subdivision of Walker's area 8A into distinct dorsal (8aD) and ventral (8aV) areas, based on analyses of both human and macaque brains. Similar subdivisions were later recognized in the marmoset (Burman et al. 2006) and capuchin monkey (Cruz-Rizzolo et al. 2011; note that these authors refer to the corresponding cytoarchitectural fields as areas 8d and 8v). The present results reinforce the view that areas 8aD and 8aV are functionally distinct.

The results of our injections in area 8aD are in general agreement with those reported by Roberts et al. (2007) for injections in the dorsal prefrontal cortex of the marmoset, which, based on the illustrated cytoarchitecture of the injection sites, most likely involved area 8aD. In particular, the label in the posterior cingulate/retrosplenial region was concentrated in ventral areas 23, 29, and 30, extending slightly into the dorsal bank of the calcarine sulcus, and there was significant labeling of the posterior parietal cortex, including the lateral intraparietal area (compare their illustrated sections with Paxinos et al. 2012). Label in the lateral temporal cortex (probably area STP) and lateral somatosensory areas (S2/PV) was apparent in 1 of our cases (CJ70-FR), but not the other. However, the pattern of connections of area 8aD in the marmoset, revealed by our data as well as by those of Roberts and colleagues, is not entirely compatible with the results of Petrides and Pandya (1999). In particular, injections in marmosets failed to reveal massive projections from auditory areas in the superior temporal gyrus and lateral fissure, which are deemed to be characteristics of area 8aD in the macaque.

One possibility to explain this discrepancy is that the present injections, which used the dextran-based tracer FR, were too small to reveal the entire connectivity of this area. However, our injections were clearly effective in revealing long-range transport, for example, from the posterior cingulate cortex, and virtually the same pattern was observed by Roberts et al. (2007) using a different tracer (cholera toxin subunit B). The results of both studies converge in showing only small numbers of labeled neurons in putative auditory areas, which were concentrated in the parabelt and in the area TPt. Another possibility is that the much larger injection reported by Petrides and Pandya (1999), using the tracer FB, labeled some neurons that, in fact, sent connections to adjacent areas. We also regard this as unlikely, given that substantial labeling of auditory cortex has been reported by many other studies with injections in the 8aD region (Barbas and Mesulam 1981; Pandya and Yeterian 1996; Romanski, Bates, et al. 1999). For example, in the analysis by Barbas and Mesulam (1981), projections from the auditory cortex accounted for 10% and 21% of neurons labeled by their middle and rostral area 8 injections, which most likely involved area 8aD.

We currently believe that the most likely explanation for this discrepancy involves a genuine species difference, with a relative increase in the emphasis of auditory connections to area 8aD in the macaque compared with the marmoset. This observation may be of interest in the context of understanding the evolution of animal communication. In particular, area TPt appears to share a degree of homology with the ill-defined “Wernicke's area”, and portions of the better-characterized planum temporale region in humans (Buxhoeveden et al. 1996; Hackett et al. 2001; Sweet et al. 2005). Future injections of tracers and functional recordings in area TPt and surrounding regions of the marmoset cortex will help to clarify the extent to which the circuitry linking high-order auditory areas to the dorsolateral prefrontal cortex may have changed during primate evolution, including the extent of the differences between New and Old World monkeys.

Connections of Area 8aV

Several previous studies, in various primate species, have reported on the connections of the frontal eye field, which includes area 8aV (e.g., Huerta et al. 1987; Barbas 1988; Schall et al. 1995; Stanton et al. 1995; Bullier et al. 1996; Tian and Lynch 1996; Petrides and Pandya 1999; Fang et al. 2005; Passarelli et al. 2011). Our results are in broad agreement with the conclusions of these reports, in showing projections from a variety of visual areas, including subdivisions of both the dorsal and ventral streams. Projections from extrastriate areas were organized according to their known visual topography (Rosa and Tweedale 2005; Rosa et al. 2005, 2009), an observation that could reflect the topography of saccade amplitudes in the frontal eye field (Blum et al. 1982; Bruce et al. 1985; Stanton et al. 1995). We also observed widespread label across multiple visuomotor areas of the dorsal occipitoparietal transition and posterior parietal cortex. The range of visual and posterior parietal areas labeled by our injections in area 8aV appears to be more expansive than that suggested by the results of Petrides and Pandya (1999) in the macaque. The broader variety of inputs observed in the marmoset would be expected from evolutionary models that propose that species with smaller brains are likely to show less marked segregation between subsystems of areas (Rilling and Insel 1999; Changizi and Shimojo 2005; Palmer and Rosa 2006a). Finally, the relative emphasis on connections of area 8aV with ventrolateral prefrontal areas, in comparison with other subdivisions of BA8, resembles observations by Watanabe-Sawaguchi et al. (1991) in the baboon.

Our observations in a case with an injection that invaded area 45 (CJ94-DY) were in substantial agreement with those in the cases where only area 8aV was involved. In the macaque, projections from the caudal inferior temporal visual cortex target area 45 (Webster et al. 1994; Bullier et al. 1996; Gerbella et al. 2010), and in the marmoset retrograde tracer injections in various visual areas result in labeled neurons in area 45 (Burman et al. 2006). These observations indicate that the functionally defined frontal eye field of the marmoset is likely to extend at least partially into cytoarchitectural area 45. Indeed, we have preliminary evidence that demonstrates dense input from visual areas after tracer injections that were entirely ventral to area 8aV (Burman and Rosa 2009b). Roberts et al. (2007) described widespread connections from visual, auditory, somatosensory, and gustatory areas to injection sites in the ventrolateral prefrontal cortex of the marmoset, which are likely to have involved areas 8aV and 45, as well as parts of area 12. In our study, only a very few neurons (2–3 per animal) were observed in the caudal auditory cortex, near the transition with areas MST and FST.

Laminar Distribution of Labeled Neurons

One intriguing aspect of our data is the paucity of putative feedback connections, i.e., projections characterized by a predominance of labeled neurons in the infragranular layers. Nevertheless, these observations are compatible with those of Barbas (1986), who reported that the laminar patterns of connections to the frontal lobe of the macaque vary according to the degree of cytoarchitectural differentiation of the projecting areas: projections from eulaminate cortices (i.e., those showing 6 well-defined layers) tended to show high proportions of labeled neurons in the supragranular layers, whereas those originating from limbic cortices, which show a more rudimentary laminar organization, tended to originate primarily in infragranular layers. Because most of the long-range projections to areas 8aD and 8aV originated from eulaminate (Barbas’ categories 4–5) areas in the occipital, temporal, parietal, and premotor cortices, the predominance of projections characterized by high %SLN values is to be expected (Medalla and Barbas 2006). Analysis of Table 4 further reveals that the few connections characterized by low %SLN values originated from limbic cortices, including the orbital insular region, area 13, and the parahippocampal areas. Whereas these observations need further validation, due to the relatively small numbers of labeled neurons, they reflect the expected laminar pattern (Barbas 1986). Interestingly, it has been determined that reciprocal projections from frontal cortex to extrastriate areas also show a supragranular bias (see Burman et al. 2006 for Discussion). Therefore, it is possible that the theoretical framework that distinguishes between feedforward, feedback, and lateral connections based on predominance of supragranular label may not be entirely adequate to characterize connections involving frontal areas. Finally, considering that we only included injections that entirely avoided the white matter, it is also possible that the paucity of infragranular labeled neurons may have been exaggerated by incomplete involvement of layer 6 in the injection sites. We note, however, that this same precaution was taken in previous work involving injections in other areas, which nevertheless revealed clear evidence of feedback-type connections (e.g., Palmer and Rosa 2006b; Rosa et al. 2009; Burman, Reser, Yu, et al. 2011).

Functional Insights From Connectivity, and Possible Relationship to Human Cortical Networks

In Old World monkeys, Brodmann's area 8 was originally confined to the rostral bank and anterior lip of the arcuate sulcus (e.g., Brodmann 1909; Vogt and Vogt 1919). The extension of area 8 to the midline cortex was proposed by Walker (1940) in an attempt to harmonize the designation of areas in macaques and humans. According to this proposal, the original BA8 was termed area 8A, whereas the new territory, where layer 4 was less distinctive, was named area 8B. However, this proposal was not universally adopted, and for many years researchers continued to depict a direct border between areas 6 and 9 (e.g., Barbas and Pandya 1989). The present results not only highlight the differences between the connections of area 8b and other subdivisions of BA8, but also the similarities between the connections of areas 8b and 9. In both the macaque and the marmoset (Barbas et al. 1999; Petrides and Pandya 1999; Burman, Reser, Yu, et al. 2011), area 9 is similar to 8b in receiving projections from the medial prefrontal, anterior, and posterior cingulate cortices, as well as from lateral and caudal orbitofrontal areas, parahippocampal cortex, and the polysensory areas along the superior temporal sulcus. Perhaps as significantly, areas 8b and 9 both have very sparse connections with the posterior parietal cortex. Overall, the similarities in connections and cytoarchitecture suggest that these areas are parts of the same functional circuit. In humans, the designation “dorsomedial prefrontal cortex” is often employed to refer to areas 8b and 9 together, and these areas may function in concert for reward processing and error monitoring during task performance, particularly in attention-demanding situations where the probability of errors is high, and where the value of rewards may vary (Mitchell 2011). In addition, there is well-documented evidence for preferential involvement of the medial part of BA8 in the integration of cognitive and limbic information, particularly in decision-related tasks in the presence of highly emotional information (Etkin et al. 2011; Mitchell 2011; Ray and Zald 2012). The distinctive connectivity of area 8b with medial frontal and anterior cingulate areas, in comparison with other subdivisions of BA8, is compatible with such a function.

With respect to areas 8aD and 8aV, our results provide further indication of their participation in spatial cognition, including working memory (Levy and Goldman-Rakic 1999), through afferent connectivity with posterior parietal and dorsal midline areas. In this context, area 8aV appears to be primarily involved in the visual modality, including control of purposive eye movements, attention, and complex assessments based on visual information (Genovesio et al. 2011). In comparison, area 8aD appears capable of integrating information from areas such as MST and 19M, which are involved in peripheral vision, with auditory and perhaps somatosensory inputs, hinting at a higher-level role in spatial cognition.

Additional clues about the functional significance of the connectional networks revealed by our results, and by previous investigation of the connections of BA8, come from studies of functional connectivity during passive states and resting conditions in macaques and humans. Mantini et al. (2011) analyzed resting state functional connectivity in functional MRI data from macaques, and identified a homolog of the human default mode network (DMN), which is active during passive awake states (Gusnard et al. 2001; Raichle et al. 2001; Greicius et al. 2003). The core of the macaque DMN is formed by areas 9/46 and 31, but it also encompasses 2 apparently separate sub-networks, 1 including areas 8b, 24, 32, and the caudal segment of STP. This sub-network mirrors the main extrinsic connectivity of area 8b in the marmoset. The second sub-network described by Mantini et al. contains areas 23, 23V, and 31, all of which had varying degrees of connectivity to subdivisions of BA8 in our study, especially areas 8aD (in the case of area 23) and 8aV (in the case of areas 31 and 23V). Thus, the differential connectivity of area 8b, on one hand, and areas 8aD and 8aV, on the other hand, could form key substrates for the different sub-circuits of the DMN. Mantini and colleagues have also described a set of 6 resting state networks in humans, based on combined electroencephalography and functional imaging. Their network 1, which corresponds to the canonical DMN, also overlaps with area 8b, whereas network 2 includes both area 8aV and subdivisions of the intraparietal sulcus.

In summary, it is likely that the connectional networks we observed in the marmoset have substantially similar homologs in other primates, including humans, a situation which facilitates the design of future experiments involving high-resolution anatomical, physiological, and lesion techniques to probe the biological bases of cognitive dysfunction. Clarifying these issues will be important for drawing correlations between clinical and experimental data. For example, functional imaging and volumetric studies have implicated BA8 among the prefrontal areas which exhibit reduced cerebral blood flow, gray matter volume, and cellular density in schizophrenia (Schultz et al. 2002; Mitelman et al. 2003), and BA8 gray matter volume is also correlated with the degree of apathy in Alzheimer's disease (Apostolova et al. 2007). Further understanding of the structural–functional basis of these pathologies requires a better understanding of the heterogeneity of area 8, including the high-resolution picture of anatomical connections afforded by studies in animal models.

Conclusions

Our data are consistent with the functional division of BA8 of the marmoset neocortex into 3 areas, each characterized by distinctive connections, and indicate considerable similarity between the New World marmoset monkey and the Old World macaque monkey. However, they also highlight some important differences, which will need to be resolved by more targeted investigation, possibly involving a comparative study that encompasses other primate species. Chief among these is the overall paucity of auditory connections to subdivisions of BA8 in the marmoset. The currently available data suggest that there may have been evolutionary modification of the relative strength and topography of connections between the posterior cortex, particularly of the temporal lobe, and the various subdivisions of BA8. Furthermore, comparison with human non-invasive imaging data suggests that the neural circuitry supporting long range, synchronous, oscillatory cortical networks appeared early in the evolution of the primate lineage, and that the marmoset may prove to be a useful model for investigation of these networks.

Supplementary Material

Supplementary material can be found at:http://www.cercor.oxfordjournals.org/.

Funding

This work was supported by project grants from the Australian Research Council (DP110101200) and National Health and Medical Research Council (525461, 545865, and 1003906).

Notes

The authors thank Prof. Michael Petrides for insightful comments on this project, Rowan Tweedale for many suggestions that substantially improved the manuscript, Amanda Worthy for help with the histological preparations, and Gregory Egan for participation in the data analysis. We gratefully acknowledge Dr Afonso Silva (NIH/NIDS) for providing us with high resolution MRI data, which were instrumental in refining the computerized reconstructions of marmoset cortex. Conflict of Interest: None declared.

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