Abstract

We found that the ventral part of the prefrontal area 46 (46v) is connectionally heterogeneous. Specifically, the rostral part (46vr) displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to area 24 and inferotemporal areas. In contrast, the caudal part (46vc) mostly displayed intraprefrontal connectivity with ventrolateral areas and robust connectivity with frontal and parietal sensorimotor areas. Based on a topographic organization of these connections, 3 fields were identified in area 46vc. A caudal field (caudal 46vc) was preferentially connected to oculomotor prearcuate (8/FEF, 45B, and 8r) and inferior parietal areas. The other 2, located more rostrally, in the bank of the principal sulcus (rostral 46vc/bank) and on the ventrolateral convexity cortex (rostral 46vc/convexity), respectively, were connected with hand/mouth-related (F5a, 44) ventral premotor areas, area SII, and the insula. However, rostral 46vc/convexity was also connected to the hand-related area AIP, whereas rostral 46vc/bank to hand/arm-related areas PFG and PG, to PGop, and to areas 11 and 24. The present data suggest a differential role in executive functions of areas 46vr and 46vc and a differential involvement of different parts of area 46vc in higher level integration for oculomotor behavior and goal-directed arm, hand, and mouth actions.

Introduction

The ventral part of the macaque area 46 (46v) is located in the ventrolateral prefrontal cortex (VLPF) where it occupies almost the entire rostrocaudal extent of the ventral bank of the principal sulcus (PS) and the immediately adjacent convexity cortex.

Area 46v hosts neurons involved in action selection, learning, and applying behavioral guiding rules for the execution of motor tasks and in controlling complex actions in terms of temporal organization and final goals (for a review, see Miller and Cohen 2001; Tanji and Hoshi 2008). Accordingly, this area appears to play an important role in controlling higher order aspects of motor behavior (see, e.g., Tanji and Hoshi 2008). The well-known rich connections with the inferior parietal lobule (IPL) and the parietal operculum from the one side, and with ventral premotor (PMv) and prearcuate oculomotor areas from the other, are considered the neural substrate for this role (see, e.g., Tanji and Hoshi 2008). However, although several studies have already described the cortical connections of area 46v (Barbas and Mesulam 1985; Barbas 1988; Barbas and Pandya 1989; Preuss and Goldman-Rakic 1989; Petrides and Pandya 2002; Gerbella et al. 2010), some aspects of its connectivity are still poorly understood.

First, indirect evidence showed that parietal, premotor, and prearcuate connections of area 46v are mostly limited to its caudal part (e.g., Petrides and Pandya 1984; Cavada and Goldman-Rakic 1989; Neal et al. 1990; Ghosh and Gattera 1995; Cipolloni and Pandya 1999; Wang et al. 2002; Rozzi et al. 2006; Borra et al. 2008; Gerbella et al. 2010; Gerbella, Belmalih, et al. 2011). These data suggest a rostrocaudal connectional heterogeneity of area 46v for which no direct evidence has been so far provided, as information on the connectivity of the rostral part of this area is still lacking.

Second, the parietal and PMv/prearcuate territories connected to area 46v consist of several distinct areas involved in markedly different aspects of sensorimotor transformations for controlling arm, hand, face, and eye movements (see, e.g., Colby 1998; Rizzolatti et al. 1998; Fogassi and Luppino 2005; Lynch and Tian 2006). Based on relatively large tracer injections in different parts of the caudal IPL, Cavada and Golman-Rakic (1989) suggested a topographic organization of the parietal connectivity of area 46v. However, the issue of whether or not the parietal and PMv/prearcuate connections of area 46v are topographically organized, that is, different parts of area 46v are preferentially connected to functionally distinct sensorimotor areas, has, so far, not been specifically addressed. This information could be very helpful for making hypotheses on the way in which this prefrontal area is involved in controlling motor behavior.

The present study examined the connectivity of area 46v based on relatively restricted tracer injections in different parts of it. Specific aims were: 1) to obtain information on the cortical connectivity of the entire rostrocaudal extent of area 46v and 2) to see whether the parietal and the PMv/prearcuate connectivity of area 46v is topographically organized. Preliminary data have been presented in an abstract form (Gerbella, Borra, et al. 2011).

Materials and Methods

Subjects, Surgical Procedures, and Selection of the Injection Sites

The experiments were carried out on 4 macaque monkeys (Macaca mulatta), in which neural tracers were injected into different parts of area 46v. Additional data from 5 macaque monkeys (2 Macaca nemestrina, 2 Macaca fascicularis, and 1 Macaca fuscata) in which neural tracers were injected in different IPL areas (LIP, AIP, PG, PFG, and PF), already presented in previous studies (Luppino et al. 1999; Rozzi et al. 2006; Borra et al. 2008), were reanalyzed herein for the purposes of the present study. Animal handling and the surgical and experimental procedures complied with the European guidelines (86/609/ EEC and 2003/65/EC Directives) and Italian laws regarding the care and use of laboratory animals and were approved by the Veterinarian Animal Care and Use Committee of the University of Parma and authorized by the Italian Health Ministry.

Under general anesthesia and aseptic conditions, each animal was placed in a stereotaxic apparatus and an incision was made in the scalp. The skull was trephined to remove the bone overlying the target region, and the dura was opened to expose the VLPF. The injection sites were chosen using the PS as an anatomical landmark and an average architectonic map of the caudal VLPF providing an estimate of the average location of areas 46v and 8r (Gerbella et al. 2007). These data were then used to estimate the location of the caudal border of area 46v with area 8r (Fig. 1A) and to select the antero–posterior (AP) level of the injection sites within area 46v. After the tracer injections, the dural flap was sutured, the bone was replaced, and the superficial tissues were sutured in layers. During surgery, hydration was provided with saline and the temperature was maintained using a heating pad. Heart rate, blood pressure, respiratory depth, and body temperature were continuously monitored. Upon recovery from anesthesia, the animals were returned to their home cages and closely monitored. Dexamethasone and prophylactic broad-spectrum antibiotics were administered pre- and postoperatively. Furthermore, analgesics were administered intra- and postoperatively.

Figure 1.

Injection sites in area 46v. (A) Composite view of all the injection sites mapped on a template hemisphere (Case 43r). Each injection site was reported on the template hemisphere based on its distance from the caudal border of area 46v; injection sites confined to the lateral bank of the PS are indicated by a downward arrow pointing to the PS. Injection sites placed in area 46vc are shown as white, black, or dark gray circles according to their location in caudal 46vc, rostral 46vc/bank, or rostral 46vc/convexity, respectively; injection sites placed in 46vr are shown as light gray circles; dashed circles indicate injection sites located in transitional zones. Dashed lines mark cytoarchitectonic borders. (B) DY injection in caudal 46vc in Case 44l; (C) DY and FB injections in rostral 46vc/bank and rostral 46vc/convexity, respectively, in Case 52l; (D) BDA injection in rostral 46vc/bank in case 52r; (E) BDA injection in area 46vr in Case 51r. Arrowheads mark the border of area 46v with areas 45A or 12r. Scale bars in B applies to BE. IA = inferior arcuate sulcus; SA = superior arcuate sulcus; C = central sulcus; LO = lateral orbital sulcus; P = principal sulcus.

Figure 1.

Injection sites in area 46v. (A) Composite view of all the injection sites mapped on a template hemisphere (Case 43r). Each injection site was reported on the template hemisphere based on its distance from the caudal border of area 46v; injection sites confined to the lateral bank of the PS are indicated by a downward arrow pointing to the PS. Injection sites placed in area 46vc are shown as white, black, or dark gray circles according to their location in caudal 46vc, rostral 46vc/bank, or rostral 46vc/convexity, respectively; injection sites placed in 46vr are shown as light gray circles; dashed circles indicate injection sites located in transitional zones. Dashed lines mark cytoarchitectonic borders. (B) DY injection in caudal 46vc in Case 44l; (C) DY and FB injections in rostral 46vc/bank and rostral 46vc/convexity, respectively, in Case 52l; (D) BDA injection in rostral 46vc/bank in case 52r; (E) BDA injection in area 46vr in Case 51r. Arrowheads mark the border of area 46v with areas 45A or 12r. Scale bars in B applies to BE. IA = inferior arcuate sulcus; SA = superior arcuate sulcus; C = central sulcus; LO = lateral orbital sulcus; P = principal sulcus.

Tracer Injections and Histological Procedures

Once the appropriate site was chosen, the retrograde tracers Fast Blue (FB, 3% in distilled water, Dr Illing Plastics GmbH, Breuberg, Germany), Diamidino Yellow (DY, 2% in 0.2 M phosphate buffer at pH 7.2, Dr Illing Plastics) and Cholera Toxin B subunit, conjugated with Alexa 488 (CTB green, CTBg) or Alexa 594 (CTB red, CTBr, 1% in 0.01 M phosphate-buffered saline at pH 7.4, Invitrogen-Molecular Probes, Eugene, OR), the mostly anterograde tracer biotinylated dextran amine (10000 MW, BDA, 10% in 0.1 M phosphate buffer, pH 7.4; Invitrogen-Molecular Probes), and the retro- and anterograde tracer dextran conjugated with tetramethylrhodamine (Fluoro-Ruby, FR, 10000 MW, or equal mixture of 10000 and 3000 MW volumes, 10% in 0.1 M phosphate buffer, pH 7.4; Invitrogen-Molecular Probes) or with lucifer yellow (10000 MW, Lucifer Yellow Dextran, LYD, 10% in 0.1 M phosphate buffer, pH 7.4; Invitrogen-Molecular Probes) were slowly pressure injected through a glass micropipette (tip diameter: 50–100 μm) attached to a 1 or 5 μL Hamilton microsyringe (Reno, NV) at about 1.2–1.5 mm below the cortical surface in the inferior frontal convexity or at different depths in the ventral bank of the PS. Table 1 summarizes the locations of injections in area 46v, the injected tracers, and their amounts.

Table 1

Location of injection sites in area 46v and type and amount of injected tracers

Case Hemisphere APa #b Sectorc Tracer Amount 
43 1.5 Caudal 46vc FR 10% 1 × 1 μL 
13.2 11 46vr CTBr 1% 1 × 1 μL 
44 2.1 Caudal 46vc DY 2% 1 × 0.2 μL 
7.2 Rostral 46vc/convexity FB 3% 1 × 0.2 μL 
51 3.6 Rostral 46vc/bank DY 2% 1 × 0.2 μL 
4.5 13 Rostral 46vc/bank and convexity FB 3% 1 × 0.2 μL 
8.7 46vr CTBg 1% 1 × 1 μL 
10.5 10 46vr BDA 10% 1 × 2 μL 
52 5.7 Rostral 46vc/bank DY 2% 1 × 0.2 μL 
5.7 Rostral 46vc/convexity FB 3% 1 × 0.2 μL 
6.9 Rostral 46vc/bank BDA 10% 1 × 2 μL 
3.9 Rostral 46vc/convexity LYD 10% 1 × 1.3 μL 
3.0 12 Caudal and rostral 46vc FR 10% 1 × 1 μL 
Case Hemisphere APa #b Sectorc Tracer Amount 
43 1.5 Caudal 46vc FR 10% 1 × 1 μL 
13.2 11 46vr CTBr 1% 1 × 1 μL 
44 2.1 Caudal 46vc DY 2% 1 × 0.2 μL 
7.2 Rostral 46vc/convexity FB 3% 1 × 0.2 μL 
51 3.6 Rostral 46vc/bank DY 2% 1 × 0.2 μL 
4.5 13 Rostral 46vc/bank and convexity FB 3% 1 × 0.2 μL 
8.7 46vr CTBg 1% 1 × 1 μL 
10.5 10 46vr BDA 10% 1 × 2 μL 
52 5.7 Rostral 46vc/bank DY 2% 1 × 0.2 μL 
5.7 Rostral 46vc/convexity FB 3% 1 × 0.2 μL 
6.9 Rostral 46vc/bank BDA 10% 1 × 2 μL 
3.9 Rostral 46vc/convexity LYD 10% 1 × 1.3 μL 
3.0 12 Caudal and rostral 46vc FR 10% 1 × 1 μL 
a

Distance of the core of the injection site (mm) from the caudal border of area 46v in the AP plane.

b

Number of the injection site in Figure 1A.

c

Location of the injection sites in area 46v (see Results).

After appropriate survival periods following the injections (28 days for BDA, FR, and LYD, and 12–14 days for FB, DY, CTBg, and CTBr), each animal was deeply anesthetized with an overdose of sodium thiopental and consecutively perfused with saline, 3.5–4% paraformaldehyde, and 5% glycerol prepared in 0.1 M phosphate buffer, pH 7.4, through the left cardiac ventricle. Each brain was then blocked coronally on a stereotaxic apparatus, removed from the skull, photographed, and placed in 10% buffered glycerol for 3 days and 20% buffered glycerol for 4 days. Finally, each brain was cut frozen into coronal sections of 60 μm thickness. In all cases in which FB, DY, CTBg, or CTBr was injected, each fifth section was mounted, air-dried, and quickly coverslipped for fluorescence microscopy. In Cases 51r and 52r, one series of each fifth section was processed to visualize BDA (incubation 60 h) using a Vectastain ABC kit (Vector Laboratories, Burlingame, CA) and 3,3’-diaminobenzidine (DAB) as a chromogen. The reaction product was intensified with cobalt chloride and nickel ammonium sulfate. In Case 43r, in which BDA was injected into another cortical area and in Case 52r, one series of each fifth section was processed to visualize FR and BDA or LYD and BDA, respectively, using the double-labeling protocol described in detail in Gerbella et al. (2010). Briefly, the sections were first processed to visualize BDA, except for a shorter incubation period in ABC solution (overnight) and then BDA was stained brown using DAB. Then, the sections were consecutively incubated overnight in avidin–biotin blocking reagent (Vector SP-2001), for 72 h at 4 °C in a primary antibody solution of rabbit anti-FR or rabbit anti-LY (1:3000; Invitrogen), 0.3% Triton, and 5% normal goat serum in 0.01 M phosphate-buffered saline at pH 7.4, and for 1 h in biotinylated secondary antibody (1:200, Vector), 0.3% Triton and 5% normal goat serum in 0.01 M phosphate-buffered saline at pH 7.4. Finally, FR or LYD labeling was visualized using the Vectastain ABC kit (Vector Laboratories) and the Vector SG peroxidase substrate kit (SK-4700, Vector) as a chromogen. With this procedure, BDA labeling was stained brown and the FR or LYD labeling was stained blue in the same tissue sections. In all cases, one series of each fifth section was stained with the Nissl method (0.1% thionin in 0.1 M acetate buffer, pH 3.7).

The cases of tracer injections in IPL areas used in the present study, which are listed in Table 2, have been already used in previous connectional studies to which the reader is referred for details on surgical and tracer injection procedures (Luppino et al. 1999; Rozzi et al. 2006; Borra et al. 2008). In the cases of injections of fluorescent tracers (DY, CTBr, Cholera Toxin B subunit, conjugated with Alexa 555 [CTB orange, CTBo, Invitrogen-Molecular Probes], True Blue [TB, 5% in distilled water, Dr Illing Plastics]), the histological procedures were similar to those described above. In cases 13l and 17r, in which wheat germ agglutinin-horseradish peroxidase conjugated (WGA-HRP, 4% in distilled water, SIGMA, St Louis, MO) was injected into areas PFG and AIP, respectively, one series of each fifth section was processed for WGA-HRP histochemistry with tetramethylbenzidine as the chromogen (Mesulam 1982).

Table 2

Injection sites in the IPL: monkey species, localization of the injections and type and amount of injected tracers

Case Species Hemisphere #a Area Tracer Amount 
13 Macaca fascicularis PFG WGA-HRP 4% 1 × 0.1 μL 
17 Macaca fuscata AIP WGA-HRP 4% 7 × 0.1 μL 
LIP TB 5% 2 × 0.2 μL 
20 Macaca nemestrina AIP DY 2% 1 × 1 μL 
27 Macaca nemestrina PG CTBr 1% 2 × 1 μL 
PF FB 3% 1 × 0.2 μL 
29 Macaca fascicularis PFG CTBo 1% 1 × 1 μL 
PG TB 5% 1 × 0.2 μL 
Case Species Hemisphere #a Area Tracer Amount 
13 Macaca fascicularis PFG WGA-HRP 4% 1 × 0.1 μL 
17 Macaca fuscata AIP WGA-HRP 4% 7 × 0.1 μL 
LIP TB 5% 2 × 0.2 μL 
20 Macaca nemestrina AIP DY 2% 1 × 1 μL 
27 Macaca nemestrina PG CTBr 1% 2 × 1 μL 
PF FB 3% 1 × 0.2 μL 
29 Macaca fascicularis PFG CTBo 1% 1 × 1 μL 
PG TB 5% 1 × 0.2 μL 
a

Number of the injection site in Figure 12.

Data Analysis

Injection Sites and Distribution of Retrogradely Labeled Neurons

The criteria used to define the injection sites and identify FB, DY, BDA, FR, and LYD labeling have been described in previous studies (Luppino et al. 2001, 2003; Rozzi et al. 2006; Gerbella et al. 2010; Gerbella, Belmalih, et al. 2011). All the injection sites used in this study were completely restricted to the cortical gray matter, involving the entire cortical thickness or at least the middle cortical layers. Using previously described cytoarchitectonic criteria (Gerbella et al. 2007; Borra et al. 2011), the injection sites were attributed to area 46v and reported, together with cytoarchitectonic borders of VLPF areas, on 2D reconstructions of the injected hemisphere. As the AP extent of area 46v was quite constant (about 16 mm) across the different hemispheres, all belonging to M. mulatta, in order to estimate the position of the injection sites within area 46v, in each case we measured the distance of the injection site from the caudal border of this area with area 8r (Table 1). Based on this measurement, the AP level of each injection site was then reported on a template hemisphere (Case 43r) in order to obtain a comparative view of their rostrocaudal distribution within area 46v (Fig. 1A).

The distribution of retrograde (for all tracer injections except BDA) and anterograde (for BDA, FR, and LYD injections) labeling was analyzed in the sections every 300 μm and plotted in sections every 600 μm, together with the outer and inner cortical borders, using a computer-based charting system. The distribution of labeling in the lateral bank of the intraparietal sulcus (IPS), in the superior temporal sulcus (STS), and in the lateral fissure (LF) was visualized in 2D reconstructions obtained using the same software, as follows (for more details, see Matelli et al. 1998). In each plotted section, the cortical region of interest was unfolded at the level of a virtual line running approximately along the border between layers III and IV. The unfolded sections were then aligned, and the labeling was distributed along the space between the 2 consecutive plotted sections (600 μm). Sections through the lateral bank of the IPS were aligned to correspond with the lateral lip of the sulcus, those through the STS to correspond with the fundus and the middle of the floor and those through the LF to correspond with the fundus of the upper bank. Using the same procedure, the distribution of the labeling observed in the VLPF after tracer injections in the IPL areas was visualized in 2D reconstructions of the PS and the VLPF convexity cortex. Data from individual sections were also imported into the 3D reconstruction software (Bettio et al. 2001) to provide volumetric reconstructions of the monkey brain, including connectional and architectonic data.

Areal Attribution of the Labeling

The criteria and maps used for the areal attribution of the labeling were mostly similar to those used in previous studies (Rozzi et al. 2006; Borra et al. 2008; Gerbella et al. 2010; Gerbella, Belmalih, et al. 2011). The prefrontal cortex was subdivided according to Carmichael and Price (1994), except for the VLPF, which was subdivided according to Gerbella et al. (2007) and Borra et al. (2011). The labeling was attributed to the agranular frontal, cingulate, and opercular frontal areas according to architectonic criteria previously described (Matelli et al. 1985, 1991; Belmalih et al. 2009). In the IPL, the gyral convexity areas were defined according to Gregoriou et al. (2006) and those of the lateral bank of the IPS according to Borra et al. (2008). For the parietal operculum, we matched our data with the functional maps of the SII region of Fitzgerald et al. (2004). The lower bank of the STS was subdivided according to Seltzer and Pandya (1978).

Quantitative Analysis and Laminar Distribution of the Labeling

In all the retrograde tracer injection cases, except for Case 52r LYD, we counted the number of labeled neurons plotted in the ipsilateral hemisphere, beyond the limits of the injected area, in sections at every 600 μm interval. Cortical afferents to area 46v were then expressed in terms of the percentage of labeled neurons found in a given cortical subdivision, with respect to the overall labeling. The LYD injection in Case 52r was excluded from this analysis because of relatively poor retrograde labeling.

Furthermore, in order to obtain information about the organization of the laminar patterns of the observed connections, the labeling attributed to a given area and reliably observed across different sections and cases was analyzed in sections at every 300 μm in terms of the following: 1) laminar distribution of the anterogradely labeled terminals (for BDA, FR, and LYD injections) and 2) the percentage of retrogradely labeled neurons located in the superficial (II–III) versus deep (V–VI) layers (s/d ratio). These data were then interpreted, when possible, according to 2 proposed models of laminar patterns of cortical connections: the functional hierarchical model, formalized by Felleman and Van Essen (1991), and the structural model, originally described for the connections of frontal areas by Barbas and colleagues (Barbas and Rempel-Clower 1997; Barbas et al. 2002).

In the functional hierarchical model, differences in laminar connectivity patterns can be used to infer possible hierarchical relationships between connected areas and can be brought back to 3 main different types of projections: “feedforward” projections, running from lower order to higher order areas; “feedback” projections, running from higher order to lower order areas and “lateral” projections, directed to areas located at the same hierarchical level. Specifically, in this model (see Fig. 3 of Felleman and Van Essen 1991), based on the laminar distribution of the retrograde labeling, the projection from the labeled area to the injected area is feedforward when labeled neurons are located mainly in the superficial layers, feedback when labeled neurons are located mainly in the deep layers, and lateral when labeled neurons are more equally distributed. Furthermore, based on the laminar distribution of the anterograde labeling, the projection from the injected to the labeled area is feedforward when labeled terminals are located mainly in layers IV and lower III, feedback, when labeled terminals are located in all layers except layer IV or primarily in superficial layers, and lateral when fairly even distributed in all cortical layers.

In the structural model, laminar connectivity patterns differ much more quantitatively rather than qualitatively, depending on the degree of structural differences (e.g., laminar differentiation and cell density) between the connected areas. Specifically, in this model (see Fig. 11 of Barbas and Rempel-Clower 1997), retro- and anterograde labeling is located: 1) mainly in the superficial layers (I–III) when the labeled area displays a higher laminar differentiation or cell density than the injected area, 2) mainly in the deep layers (IV–VI) when the labeled area displays a lower laminar differentiation or neuronal density than the injected area, and 3) almost equally in both superficial and deep layers when the labeled and the injected area display a similar laminar differentiation or cell density.

Results

Definition of Area 46v and Injection Site Locations

Area 46v, as defined in the present study, corresponds to the ventral part of Walker’s (1940) area 46 and occupies almost the entire extent of the ventral bank of the PS and the immediately adjacent VLPF convexity cortex (Fig. 1A). Different architectonic subdivisions of this area have been proposed by other researchers (Barbas and Pandya 1989; Preuss and Goldman-Rakic 1991; Petrides and Pandya 1994, 2002). Nevertheless, in previous studies (Gerbella et al. 2007; Borra et al. 2011), we found that a cell-dense layer III, almost homogeneously populated by relatively small pyramids, a well developed and cell-dense layer IV, and a layer V densely populated by small pyramids, are major unifying architectonic features of area 46v that distinguish it from the neighboring VLPF areas.

The injection sites presented in this study were all entirely located within area 46v at different rostrocaudal levels, involving either the VLPF convexity cortex and, in some cases, the shoulder of the PS, or the bank of the PS (Fig. 1A–E).

As will be shown later, the results first provide evidence of 2 markedly distinct connectivity patterns displayed by different parts of area 46v. One, characterized by rich connections with PMv/prearcuate and parietal areas, was observed after the injections in the caudal half of area 46v, that is, within about 8 mm from its caudal border with area 8r, and the other, characterized by the virtual absence of these connections, was observed after the injections in the rostral half (light gray circles in Fig. 1A). These 2 parts of area 46v will be designated as “ventrocaudal” (46vc) and “ventrorostral” (46vr) 46v, respectively. Furthermore, the results showed a topographic organization of the connections of area 46vc, with 3 different parietal and PMv/prearcuate connectivity patterns displayed by different parts of it. One was observed after injections in the caudal part of area 46vc (white circles in Fig. 1A), that is, within about 3 mm from its caudal border, and the other 2 were observed after injections in more rostral sites, that is, from about 3 to about 8 mm rostral to its caudal border, in the bank of the PS (black circles in Fig. 1A) or in the VLPF convexity cortex (dark gray circles in Fig. 1A). These 3 zones of area 46vc are designated herein as “caudal 46vc, rostral 46vc/bank, and rostral 46vc/convexity,” respectively.

Connections of Area 46vc

Injections in the Caudal 46vc

Two tracer injections (Cases 44l DY and 43r FR) were placed into the caudal 46vc, involving the upper part of the bank of the PS and its shoulder (e.g., Fig. 1B). The results from these 2 cases were quite similar and are shown in Figures 2 and 3 and in Table 3.

Table 3

Percent distribution (%) and total number (n) of labeled neurons observed following tracer injections in area 46v

Injected area Caudal 46vc Rostral 46vc/bank Rostral 46vc/convexity 46vr 
Case C43r FR C44l DY Mean C51l DY C52l DY Mean C44l FB C52l FB Mean C43l CTBr C51l CTBg Mean 
VLPF and DLPF             
    10    1.1 1.7 1.4 
    12r 11.3 19.6 15.4 3.2 2.8 24.1 25.2 24.6 19.5 14.4 16.9 
    46vr 2.2 1.5 22.8 15.9 19.4 11.1 12.7 11.9 
    46vc 12.4 19 15.7 
    45A 4.6 3.7 1.9 1.9 1.4 2.2 
    12l 1.2 2.6 2.7 2.6 
    9/8B 1.2 1.3 7.9 6.9 
    46d 8.8 5.2 7.2 4.7 5.9 3.8 4.7 4.2 5.3 6.6 
Prearcuate             
    45B 17 19.5 18.2 2.5 4.5 3.5 3.8 2.4 3.1 
    8r 9.8 7.2 8.5 1.7 1.1 
    8/FEF 19.6 26.5 23 
Orbitofrontal             
    11 8.2 6.6 1.8 1.3 17.9 16.4 17.1 
    12m 1.3 1.1 1.2 2.5 2.2 1.5 1.6 1.5 
    13 4.8 5.8 5.3 
Total prefrontal 74.5 84.2 79.3 46.2 40.6 43.4 44.1 49.7 46.9 81.8 79.2 80.5 
Caudal frontal             
    44 2.2 2.1 6.4 5.2 5.8 8.4 5.3 6.8 2.4 1.5 
    F5a 7.2 5.3 6.2 19.8 14.8 17.3 
    F5c 
    F5p 1.9 1.7 1.8 
    F6, supplementary eye field 1.2 1.2 1.6 1.3 1.1 1.2 
    GrFO 1.1 2.8 1.9 2.9 1.7 2.3 2.9 1.9 
    PrCO 1.3 2.2 1.7 1.7 2.1 1.9 
Total caudal frontal 4.2 2.5 3.4 20.4 18.9 19.7 34.7 26 30.3 2.8 7.1 4.9 
Parietal             
    LIP 12.2 9.1 10.6 
    AIP 7.8 5.5 6.6 
    PF 1.1 1.2 1.1 
    PFG 5.6 5.5 5.5 
    PG 7.9 5.6 6.8 
    PGop 3.5 3.9 3.6   
    SII 3.4 6.3 4.8 4.6 6.7 5.6 
Total parietal 12.2 9.2 10.7 21.4 21.8 21.6 14.4 14.9 14.7 1.8 1.2 
Temporal             
    IPa, TEa/m 2.7 1.8 1.6 1.2 6.2 6.1 
    Superior temporal polysensory 
    FST/MT 2.4 1.6 1.9 
Total temporal 5.8 2.8 4.3 1.3 1.2 * 2.2 1.5 6.8 6.6 6.7 
24 2.7 1.1 1.9 5.9 6.6 6.2 1.2 1.1 7.4 4.8 6.1 
Insula 5.1 10.8 7.9 5.1 5.5 
Total cells (n5651 9622  6875 10 582  22 216 10 582  8701 11 711  
Injected area Caudal 46vc Rostral 46vc/bank Rostral 46vc/convexity 46vr 
Case C43r FR C44l DY Mean C51l DY C52l DY Mean C44l FB C52l FB Mean C43l CTBr C51l CTBg Mean 
VLPF and DLPF             
    10    1.1 1.7 1.4 
    12r 11.3 19.6 15.4 3.2 2.8 24.1 25.2 24.6 19.5 14.4 16.9 
    46vr 2.2 1.5 22.8 15.9 19.4 11.1 12.7 11.9 
    46vc 12.4 19 15.7 
    45A 4.6 3.7 1.9 1.9 1.4 2.2 
    12l 1.2 2.6 2.7 2.6 
    9/8B 1.2 1.3 7.9 6.9 
    46d 8.8 5.2 7.2 4.7 5.9 3.8 4.7 4.2 5.3 6.6 
Prearcuate             
    45B 17 19.5 18.2 2.5 4.5 3.5 3.8 2.4 3.1 
    8r 9.8 7.2 8.5 1.7 1.1 
    8/FEF 19.6 26.5 23 
Orbitofrontal             
    11 8.2 6.6 1.8 1.3 17.9 16.4 17.1 
    12m 1.3 1.1 1.2 2.5 2.2 1.5 1.6 1.5 
    13 4.8 5.8 5.3 
Total prefrontal 74.5 84.2 79.3 46.2 40.6 43.4 44.1 49.7 46.9 81.8 79.2 80.5 
Caudal frontal             
    44 2.2 2.1 6.4 5.2 5.8 8.4 5.3 6.8 2.4 1.5 
    F5a 7.2 5.3 6.2 19.8 14.8 17.3 
    F5c 
    F5p 1.9 1.7 1.8 
    F6, supplementary eye field 1.2 1.2 1.6 1.3 1.1 1.2 
    GrFO 1.1 2.8 1.9 2.9 1.7 2.3 2.9 1.9 
    PrCO 1.3 2.2 1.7 1.7 2.1 1.9 
Total caudal frontal 4.2 2.5 3.4 20.4 18.9 19.7 34.7 26 30.3 2.8 7.1 4.9 
Parietal             
    LIP 12.2 9.1 10.6 
    AIP 7.8 5.5 6.6 
    PF 1.1 1.2 1.1 
    PFG 5.6 5.5 5.5 
    PG 7.9 5.6 6.8 
    PGop 3.5 3.9 3.6   
    SII 3.4 6.3 4.8 4.6 6.7 5.6 
Total parietal 12.2 9.2 10.7 21.4 21.8 21.6 14.4 14.9 14.7 1.8 1.2 
Temporal             
    IPa, TEa/m 2.7 1.8 1.6 1.2 6.2 6.1 
    Superior temporal polysensory 
    FST/MT 2.4 1.6 1.9 
Total temporal 5.8 2.8 4.3 1.3 1.2 * 2.2 1.5 6.8 6.6 6.7 
24 2.7 1.1 1.9 5.9 6.6 6.2 1.2 1.1 7.4 4.8 6.1 
Insula 5.1 10.8 7.9 5.1 5.5 
Total cells (n5651 9622  6875 10 582  22 216 10 582  8701 11 711  

Note: /, injected area; - , no labeling; * , labeling <1%.

Figure 2.

Distribution of the retrograde and anterograde labeling observed in Cases 44l DY and 43r FR, respectively, following injections in caudal 46vc. The labeling is shown in dorsolateral and medial views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the lateral bank of the IPS (lower part). For the retrograde labeling, each dot corresponds to one labeled neuron, for the anterograde labeling the dot density is proportional to the density of the observed labeled terminals (one dot is equivalent to ∼15–25 labeled terminals). Each 2D reconstruction of the IPS was aligned to correspond with the lip of the bank, indicated by a continuous line; the dotted line corresponds to the fundus. Arrows mark AP stereotaxic level = 0. The location of each tracer injection is shown as a white area on the dorsolateral view of the hemisphere. ag = annectant gyrus; Cg = cingulate sulcus; IO = inferior occipital sulcus; IPS = intraparietal sulcus; L = lateral fissure; Lu = lunate sulcus; ST = superior temporal sulcus. Other abbreviations as in Figure 1.

Figure 2.

Distribution of the retrograde and anterograde labeling observed in Cases 44l DY and 43r FR, respectively, following injections in caudal 46vc. The labeling is shown in dorsolateral and medial views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the lateral bank of the IPS (lower part). For the retrograde labeling, each dot corresponds to one labeled neuron, for the anterograde labeling the dot density is proportional to the density of the observed labeled terminals (one dot is equivalent to ∼15–25 labeled terminals). Each 2D reconstruction of the IPS was aligned to correspond with the lip of the bank, indicated by a continuous line; the dotted line corresponds to the fundus. Arrows mark AP stereotaxic level = 0. The location of each tracer injection is shown as a white area on the dorsolateral view of the hemisphere. ag = annectant gyrus; Cg = cingulate sulcus; IO = inferior occipital sulcus; IPS = intraparietal sulcus; L = lateral fissure; Lu = lunate sulcus; ST = superior temporal sulcus. Other abbreviations as in Figure 1.

Figure 3.

Distribution of the retrograde labeling observed in Case 44l DY (upper part) and of the anterograde labeling observed in Case 43r FR (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (af and a′–f′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. MO = medial orbital sulcus; OT = occipitotemporal sulcus. Other conventions and abbreviations as in Figures 1 and 2.

Figure 3.

Distribution of the retrograde labeling observed in Case 44l DY (upper part) and of the anterograde labeling observed in Case 43r FR (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (af and a′–f′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. MO = medial orbital sulcus; OT = occipitotemporal sulcus. Other conventions and abbreviations as in Figures 1 and 2.

In the prefrontal cortex (Fig. 2), most of the observed labeling (both retro- and retro-anterograde) was located in the caudal VLPF. Specifically, there were dense connections with areas 45A, 8r, and the caudal part of area 12r and even denser ones with prearcuate areas 45B and 8/FEF (Fig. 3, sections ae and a′–e′), where the highest percentages of retrogradely labeled cells were found (Table 3). A few clusters of marked cells were located more rostrally in areas 46vr and in rostral area 12r. Relatively dense labeling was observed in the dorsolateral prefrontal (DLPF) area 46d, mostly in its caudal part.

Outside the prefrontal cortex, 2 frontal sectors were relatively weakly labeled: one in the fundal inferior arcuate area 44 and the other dorsorostrally in the dorsal premotor cortex, which corresponded to the supplementary eye field (Schlag and Schlag-Rey 1987). In the parietal cortex, dense-labeled cells and terminals were observed in the lateral bank of the IPS, in area LIP (Figs 2 and 3, sections f and f′). In the temporal cortex, relatively weak labeling was observed in the STS. Specifically, sparse labeling was located in areas TEa/m, TEO, IPa, and in the superior temporal polysensory area, and a few clusters of labeled cells were located more caudally, in areas FST and MT. Finally, a weak connection was found with the cingulate area 24, mostly with the cingulate gyrus (areas 24a and 24b).

The laminar distribution of the retro- and anterograde labeling in the various areas connected to caudal 46vc fell within 2 main patterns. One pattern, characterized by labeled cells and terminals that were almost equally distributed in the superficial and deep cortical layers, was observed in all labeled lateral prefrontal areas. In the Felleman and Van Essen’s (1991) model, this pattern is the one expected for connections between areas located at a similar hierarchical level (lateral projection). In the structural model by Barbas and Rempel-Clower (1997) is the one expected for the connections of areas of a similar structure. The other pattern, characterized by labeled cells considerably denser in the superficial layers (s/d ratio >66%) and labeled terminals located primarily in layers I–III and absent in layer IV, was observed in LIP (Fig. 4A,F). According to the Felleman and Van Essen’s model, this pattern suggests that, based on the distribution of the retrograde labeling, LIP sends feedforward projections to caudal 46vc and, based on the distribution of the anterograde labeling, caudal 46vc sends feedback projections to LIP. In relation to the Barbas and Rempel-Clower’s (1997) model, this pattern, based on the distribution of both the retrograde and anterograde labeling, fits well with the observations of Medalla and Barbas (2006) that LIP displays a higher cell density than area 46v.

Figure 4.

Examples of laminar patterns of retrograde and anterograde labeling observed following injections in area 46v. In each photomicrograph, is indicated the area in which the labeling was observed and, in parentheses, the injected zone of area 46v. A was taken from Case 43r FR, B, and D from Case 52r LYD, C from Case 52r BDA, E from Case 51r BDA, F from Case 44l DY, G from Case 44l FB, H and I from Case 52l DY, and J from Case 43l CTBr. Scale bar in A applies to all photomicrographs.

Figure 4.

Examples of laminar patterns of retrograde and anterograde labeling observed following injections in area 46v. In each photomicrograph, is indicated the area in which the labeling was observed and, in parentheses, the injected zone of area 46v. A was taken from Case 43r FR, B, and D from Case 52r LYD, C from Case 52r BDA, E from Case 51r BDA, F from Case 44l DY, G from Case 44l FB, H and I from Case 52l DY, and J from Case 43l CTBr. Scale bar in A applies to all photomicrographs.

Injections in the Rostral 46vc/Bank

Three tracer injections (Case 51l DY, Case 52l DY, and Case 52r BDA) were placed into the bank of the PS at different AP levels of the rostral part of area 46vc. In Cases 51l and 52l (Fig. 1C), the cores of the DY injection sites were completely confined to the bank of the PS. In Case 52r, the BDA injection site, although mostly confined to the bank, also marginally involved the shoulder (Fig. 1D). All these injections showed a connectivity pattern that was quite consistent across the different cases and which was different from the pattern observed for caudal 46vc. The results of Cases 52l DY and 52r BDA are shown in Figures 5 and 6. Table 3 shows the percentage distribution of the retrograde labeling observed in Cases 51l DY and 52l DY.

Figure 5.

Distribution of the retrograde and anterograde labeling observed in Cases 52l DY and 52r BDA, respectively, following injections in rostral 46vc/bank. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the LF and of the IPS (lower part). Each 2D reconstruction of the LF was aligned to correspond with the dorsal border of the insula indicated by a straight dotted line; the continuous line marks the lip of the bank and the curved dotted line below the fundus marks the border of the insula with the lower bank of the sulcus. Arrows mark the levels of AP = 0, of the rostral tip of the IPS (IP), and of the rostralmost level of the central sulcus (C). UBLF = upper bank of the lateral fissure. Other conventions and abbreviations as in Figures 1 and 2.

Figure 5.

Distribution of the retrograde and anterograde labeling observed in Cases 52l DY and 52r BDA, respectively, following injections in rostral 46vc/bank. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the LF and of the IPS (lower part). Each 2D reconstruction of the LF was aligned to correspond with the dorsal border of the insula indicated by a straight dotted line; the continuous line marks the lip of the bank and the curved dotted line below the fundus marks the border of the insula with the lower bank of the sulcus. Arrows mark the levels of AP = 0, of the rostral tip of the IPS (IP), and of the rostralmost level of the central sulcus (C). UBLF = upper bank of the lateral fissure. Other conventions and abbreviations as in Figures 1 and 2.

Figure 6.

Distribution of the retrograde labeling observed in Case 52l DY (upper part) and of the anterograde labeling observed in Case 52r BDA (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ai and a′–i′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site, indicated for Case 52l DY by an arrowhead. Conventions and abbreviations as in Figures 1 and 2.

Figure 6.

Distribution of the retrograde labeling observed in Case 52l DY (upper part) and of the anterograde labeling observed in Case 52r BDA (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ai and a′–i′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site, indicated for Case 52l DY by an arrowhead. Conventions and abbreviations as in Figures 1 and 2.

In the prefrontal cortex (Fig. 5), the most densely labeled sector was area 46vr (Fig. 6, sections a and a′). In the VLPF, additional connections involved areas 12r (mostly the intermediate part), 45A, 45B and, although weakly, area 8r (Fig. 6, sections ad and a′–d′). No labeling was observed in area 8/FEF. As after injections placed in caudal 46vc, a relatively dense connection was observed with the caudal part of area 46d. Rich labeling was observed in orbitofrontal area 11 and weaker labeling in area 12m (Fig. 6, sections a, a′, and b′).

A high proportion of marked cells and rich anterograde labeling were observed outside the prefrontal cortex (Fig. 5; Table 3). In the PMv, there were dense connections with area F5a, in the anterior part of the postarcuate bank and with the adjacent fundal area 44 (Fig. 6, sections e and f and e′ and f′). Marked cells were almost equally distributed between these 2 areas (Table 3). Weaker labeling was located in area F5p, in the posterior part of the postarcuate bank, and in the opercular frontal areas GrFO and PrCO (Fig. 6, sections e and f, and e′ and f′). Sparse labeled cells and terminals were observed in areas F5c and F6. In the parietal cortex, the percentage of labeled cells was similar to that observed in the PMv (Table 3). Specifically, relatively dense retrograde or anterograde labeling was observed in the IPL convexity areas PFG and PG (Fig. 6, sections h and i and h′ and i′), also extending to the caudal part of the parietal operculum, mostly in the location of area PGop (Pandya and Seltzer 1982). A relatively dense connection was also found more rostrally in the parietal operculum, mostly at an AP level between that of the rostral most part of the IPS and that of the central sulcus (Figs 5 and 6, sections g and g′). A comparison with functional maps published by Fitzgerald et al. (2004) suggests that this labeling likely involved mostly the hand representation of the SII region. Only very few sparsely labeled cells or terminals were located in AIP. Rich and extensive retro- or anterograde labeling was located in the insular cortex (Figs 5 and 6, sections g and g′), most likely involving the dysgranular and the granular insula (Mesulam and Mufson 1982), and a dense connection was also observed with area 24 (Fig. 6, section e), mostly with the cingulate gyrus (areas 24a and 24b). Only a few marked cells were found in the inferotemporal area TEa/m.

In all frontal areas, except for the orbitofrontal cortex, retro- and anterograde labeling was almost equally distributed in the superficial and deep cortical layers. In areas 11 and 12m, the labeled cells and terminals tended to be denser in the deep layers (s/d ratio <33%). In the Felleman and Van Essen’s (1991) model, this pattern of retrograde labeling suggests that areas 11 and 12m send feedback projections to rostral 46vc/bank, whereas the observed pattern of anterograde labeling is not provided. In the Barbas and Rempel-Clower’s (1997) model, this pattern is exactly the one expected in less differentiated orbitofrontal areas after tracer injections in more differentiated VLPF areas. A similar pattern was observed in area 24. In the connected inferior and opercular parietal areas and in the insular cortex, the laminar distribution of the labeling was similar to that observed in LIP after the injections in the caudal area 46vc (Fig. 4C,H, and I).

Injections in the Rostral 46vc/Convexity

Three tracer injections (Cases 44l FB, 52l FB, and 52r LYD) were placed into the rostral part of area 46vc, involving the VLPF convexity cortex and, to a variable extent across the cases, the shoulder of the bank of the PS (e.g., Fig. 1C). The results, as shown in Figures 7–9, displayed a connectivity pattern that was quite consistent across the different cases but which was different from that observed for caudal 46vc and, for several aspects, was also different from that observed after the injections in the rostral 46vc/bank. Table 3 shows the percentage distribution of the retrograde labeling observed in Cases 44l FB and 52l FB. As noted in the Materials and Methods, Case 52r LYD was analyzed only in terms of distribution of anterograde labeling.

Figure 7.

Distribution of the retrograde labeling observed in Cases 44l FB and 52l FB and of the anterograde labeling observed in Case 52r LYD following injections in rostral 46vc/convexity. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres. Other conventions and abbreviations as in Figures 1 and 2.

Figure 7.

Distribution of the retrograde labeling observed in Cases 44l FB and 52l FB and of the anterograde labeling observed in Case 52r LYD following injections in rostral 46vc/convexity. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres. Other conventions and abbreviations as in Figures 1 and 2.

Figure 8.

Distribution of the retrograde labeling observed in Cases 44l FB and 52l FB and of the anterograde labeling observed in Case 52r LYD, shown in 2D reconstructions of the IPS (upper part) and of the LF (lower part). Conventions and abbreviations as in Figures 2 and 5.

Figure 8.

Distribution of the retrograde labeling observed in Cases 44l FB and 52l FB and of the anterograde labeling observed in Case 52r LYD, shown in 2D reconstructions of the IPS (upper part) and of the LF (lower part). Conventions and abbreviations as in Figures 2 and 5.

Figure 9.

Distribution of the retrograde labeling observed in Case 44l FB (upper part) and of the anterograde labeling observed in Case 52r LYD (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ai and a′–i′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. Conventions and abbreviations as in Figures 1 and 2.

Figure 9.

Distribution of the retrograde labeling observed in Case 44l FB (upper part) and of the anterograde labeling observed in Case 52r LYD (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ai and a′–i′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. Conventions and abbreviations as in Figures 1 and 2.

In the prefrontal cortex (Fig. 7), a rich connection was observed with area 46vr and an even richer one with area 12r (Fig. 9, sections a and b and a′ and b′). In this last area, labeled cells and terminals were mostly concentrated in its intermediate part. Only relatively weak labeling was observed in other VLPF areas. As for the other parts of area 46vc, a relative dense connection was found with the caudal part of area 46d (Fig. 9, sections d and d′). Relatively weak labeling was observed in orbitofrontal areas 11 and 12m (Fig. 9, sections b and a′ and b′).

Outside the prefrontal cortex rich connections were observed with the PMv areas F5a and 44 (Fig. 9, sections e and f and e′ and f′). Unlike the rostral 46vc/bank, the percentage of labeled cells found in these 2 areas tended to be higher, especially for Case 52l FB in area F5a (Table 3). Sparse labeled cells or terminals were found in areas F5p and F5c and a weak connection was observed with area F6. Relatively weak connections were also observed with the opercular frontal areas GrFO and PrCO (Figs 8 and 9, sections d and d′ and e′). In the parietal cortex, the percentage of marked cells was considerably lower than that in the PMv (Table 3). Except for a weak connection with the rostral IPL convexity area PF, virtually all the parietal labeling was concentrated in 2 zones: one corresponding to area AIP, the other mostly corresponding to the location of the hand field of SII (Figs 8 and 9, sections h and i, and g′–i′).

Finally, dense retro- or anterograde labeling was observed in the insular cortex, most likely in the dysgranular insula (Figs 8 and 9, sections g and g′), and sparse retro- or anterograde labeling was found in the inferotemporal cortex (areas IPa and TEa/m) and in cingulate area 24, mostly areas 24a and 24b.

The laminar distribution of the retro- or anterograde labeling observed in the various areas connected to rostral 46vc/convexity was very similar to that observed after the injections in the other 2 area 46vc sectors. Specifically, in all frontal areas except for the orbitofrontal cortex, retro- and anterograde labeling was almost equally distributed in the superficial and deep cortical layers, whereas in areas 11 and 12m, the labeled cells and terminals tended to be denser in the deep layers (s/d ratio <33%). In area AIP, in SII and in the insular cortex, labeled cells were considerably denser in the superficial layers (s/d ratio >66%) and labeled terminals were richer in layers I–III and absent in layer IV (Fig. 4B,D, and G).

“Transitional” Injections in Area 46vc

Two injection sites (Cases 52r FR and 51l FB) showed a labeling distribution compatible with a transition between the different connectivity patterns described above. In Case 52r FR, the injection site, in the VLPF convexity cortex, about 3-mm rostral to the caudal border of area of 46v, displayed a connectivity pattern that was intermediate between that of caudal 46vc and that of rostral 46vc/convexity. For example, in the frontal lobe, the observed retro- and anterograde labeling was almost equally distributed between both the prearcuate and postarcuate areas and in the parietal cortex between both areas LIP and AIP. In Case 51l FB, the injection site, which was about 4.5-mm rostral to the caudal border of area 46v and involved the shoulder and the uppermost part of the bank of the PS, displayed a connectivity pattern that was intermediate between that of rostral 46vc/convexity and that of the rostral 46vc/bank, characterized, for example, by retrograde labeling involving both AIP and IPL convexity areas.

Connections of Area 46vr

Three tracer injections were placed in the rostral half of area 46v at different AP levels, involving the VLPF convexity cortex and the shoulder of the bank of the PS (Case 43l CTBr) or the shoulder and the upper part of the bank (Cases 51l CTBg and 51r BDA, e.g., Fig. 1E). The results, as shown in Figures 10 and 11, showed a connectivity pattern that was basically quite consistent across the different cases but which was markedly different from that observed for area 46vc. Table 3 shows the percentage distribution of the retrograde labeling observed in Cases 43lr CTBr and 51l CTBg.

Figure 10.

Distribution of the retrograde and anterograde labeling observed in Cases 51l CTBg and 51r BDA, respectively, following injections in area 46vr. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the STS (lower part). Each 2D reconstruction of the STS was aligned to correspond with the fundus and middle of the floor. The dotted lines indicate the fundus and the upper and lower edges of the floor, the continuous lines indicate the lips of the sulcus. Conventions and abbreviations as in Figures 1 and 2.

Figure 10.

Distribution of the retrograde and anterograde labeling observed in Cases 51l CTBg and 51r BDA, respectively, following injections in area 46vr. The labeling is shown in dorsolateral, medial, and bottom views of the 3D reconstructions of the injected hemispheres (upper part) and in 2D reconstructions of the STS (lower part). Each 2D reconstruction of the STS was aligned to correspond with the fundus and middle of the floor. The dotted lines indicate the fundus and the upper and lower edges of the floor, the continuous lines indicate the lips of the sulcus. Conventions and abbreviations as in Figures 1 and 2.

Figure 11.

Distribution of the retrograde labeling observed in Case 51l CTBg (upper part) and of the anterograde labeling observed in Case 51r BDA (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ah and a′–h′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. Conventions and abbreviations as in Figures 1 and 2.

Figure 11.

Distribution of the retrograde labeling observed in Case 51l CTBg (upper part) and of the anterograde labeling observed in Case 51r BDA (lower part) shown in drawings of coronal sections. Sections are shown in a rostral to caudal order (ah and a′–h′). For each case, a dorsolateral view of the injected hemisphere shows the levels at which the sections were taken and the location of the injection site. Conventions and abbreviations as in Figures 1 and 2.

Most of the labeled cells and terminals after injections in 46vr were observed in the prefrontal cortex (Figs 10 and 11, sections af and a′–f’). Specifically, although with quantitative differences between the cases, 2 VLPF areas were the most densely labeled: 46vc and 12r. Weaker connections were observed with areas 10, 45A, 45B, and 12l. Dense connections were found with the dorsal prefrontal areas 46d and 9/8B. In Case 51r BDA, the anterograde labeling observed in areas 9/8B and 45A appeared relatively weak with respect to the retrograde labeling observed in these same areas in the other 2 cases. However, as this observation is based on only one anterograde tracer injection, it cannot provide firm evidence for a possible unbalance in the reciprocity of these connections. In the orbitofrontal cortex, a strong connection was found with area 11 and a weaker, but relatively dense one, with area 13 (Fig. 11, sections bd and c′ and d′). Weaker labeling was located in area 12m.

Outside the prefrontal cortex, the only substantially labeled regions were the cingulate area 24 and the inferotemporal cortex, where the retro- or anterograde labeling involved areas TEa/m and IPa (Figs 10 and 11, sections eh and g′ and h′). Except for a weak connection with area 44 and GrFO observed in Case 51l CTBg (the most caudal of the 3 injection sites), in all the cases labeling in the caudal frontal and parietal cortex was virtually absent.

The laminar distribution of the retro- and anterograde labeling in the various connected lateral prefrontal and orbitofrontal areas and in area 24 was similar to that observed for all the 3 area 46vc sectors. In STS areas, the labeled cells were denser in the superficial layers (s/d ratio >66%) and labeled terminals involved layers I–III and VI, though richer in layer III and even more so in layer I (Fig. 4E,J). This pattern was quite similar to that observed in the labeled parietal areas after tracer injections in area 46vc.

Parietal Connectivity of Area 46vc: Indirect Data

The results described above from tracer injections in area 46vc show that the distribution of the labeling in the IPL markedly differed according to the position of the injection site. In order to obtain additional evidence for the possible topographic organization of the IPL connectivity of area 46vc, we analyzed the distribution of the prefrontal retrograde labeling observed in previous studies after injections in different IPL areas in more detail (Luppino et al. 1999; Rozzi et al. 2006; Borra et al. 2008).

The results of this analysis, as shown in Figure 12, are in full agreement with the present data from tracer injections in area 46v. First, after tracer injections in any of the IPL areas connected to area 46v, virtually all the retrograde labeling was confined to its caudal half (area 46vc), despite differences in the AP extent across different monkey species. Second a clear segregation of area 46vc territories labeled after the injections in different IPL areas was observed. Specifically: 1) after a tracer injection in area LIP (Case 17l TB) the labeled cells in area 46vc were confined to its caudal part (caudal 46vc); 2) after tracer injections in either area PG (Cases 27r CTBr and 29r TB) or in area PFG (Cases 13l WGA-HRP and 29r CTBo) all dense retrograde labeling was virtually all concentrated within the bank of the PS in the rostral part of area 46vc (rostral 46vc/bank); 3) after injections in AIP (Cases 17r WGA-HRP and 20l DY) very dense retrograde labeling was located in the rostral part of area 46vc along the shoulder of the PS and in the adjacent VLPF convexity cortex (rostral 46vc/convexity), also extending laterally into the intermediate part of area 12r; and 4) after a tracer injection in area PF (Case 27r FB) a relatively weak connection was observed with the rostral part of area 46vc corresponding with the PS shoulder (rostral 46vc/convexity).

Figure 12.

Upper part: summary view of the location of the injection sites in IPL areas LIP, AIP, PF, PG, and PFG plotted onto a dorsolateral view of a single hemisphere. Injection sites in LIP and AIP are indicated by downward arrows pointing to the IPS. Arrowheads pointing to the IPS mark AP levels-2 and 6, corresponding to the caudal and rostral limits of AIP, respectively. Lower part: 2D reconstructions of the PS and of the adjacent VLPF convexity cortex showing the distribution of the retrograde labeling observed in the VLPF following the injections in the IPL areas. Each 2D reconstruction was aligned to correspond to the fundus of the PS, indicated by a straight dotted line. In each reconstruction, the dashed line marks the border of area 46v and the arrow marks the middle of the AP extent of area 46v. LBPS = lower bank of the PS; UBPS = upper bank of the PS. Conventions and other abbreviations as in Figures 1 and 2.

Figure 12.

Upper part: summary view of the location of the injection sites in IPL areas LIP, AIP, PF, PG, and PFG plotted onto a dorsolateral view of a single hemisphere. Injection sites in LIP and AIP are indicated by downward arrows pointing to the IPS. Arrowheads pointing to the IPS mark AP levels-2 and 6, corresponding to the caudal and rostral limits of AIP, respectively. Lower part: 2D reconstructions of the PS and of the adjacent VLPF convexity cortex showing the distribution of the retrograde labeling observed in the VLPF following the injections in the IPL areas. Each 2D reconstruction was aligned to correspond to the fundus of the PS, indicated by a straight dotted line. In each reconstruction, the dashed line marks the border of area 46v and the arrow marks the middle of the AP extent of area 46v. LBPS = lower bank of the PS; UBPS = upper bank of the PS. Conventions and other abbreviations as in Figures 1 and 2.

Discussion

The present study examined the cortical connectivity of area 46v. There were 2 major findings. First, the caudal and the rostral parts of area 46v, designated as 46vc and 46vr, respectively, were found to be markedly distinct in terms of cortical connections, in which only area 46vc displayed substantial connections with parietal and premotor/prearcuate areas. Second, the parietal and the premotor/prearcuate connectivity of area 46vc displayed a clear topographic organization.

Cortical Connections of Area 46v

The present data, summarized in Figure 13, indicate that area 46vr, or at least that part of it including the upper part of the bank of the PS and the adjacent convexity cortex, showed an homogeneous connectivity pattern characterized by very strong intraprefrontal connections with VLPF, DLPF, and orbitofrontal areas and substantial extraprefrontal connections that only involved inferotemporal areas of the STS and area 24. This connectivity pattern markedly differed from that of area 46vc, which, in general, displayed weaker connections with the DLPF and orbitofrontal areas, very poor temporal connectivity, and substantial connections with parietal and PMv/prearcuate areas.

Figure 13.

Summary view of the cortical connectivity of the connectionally distinct area 46v sectors identified in the present study. In the left column, drawings of an hemisphere show the major sources of ipsilateral cortical projections to each sector. The injected sectors are indicated by a hatched zone and, based on the data listed in Table 3, areas hosting >5% and those hosting 1–5% of the observed labeled cells are shown in dark and light gray, respectively. In the right column, diagrams summarize for each sector the hierarchical relationships that can be inferred from the observed laminar patterns of its connections. In each diagram, areas that send feedforward projections to and receive feedback projections from a given sector are indicated with white boxes in the lower part, areas displaying lateral connections are indicated with light gray boxes in the middle part, and areas that receive feedforward projections from and send feedback projections to that sector are indicated with dark gray boxes in the upper part. Abbreviations as in Figures 1 and 2.

Figure 13.

Summary view of the cortical connectivity of the connectionally distinct area 46v sectors identified in the present study. In the left column, drawings of an hemisphere show the major sources of ipsilateral cortical projections to each sector. The injected sectors are indicated by a hatched zone and, based on the data listed in Table 3, areas hosting >5% and those hosting 1–5% of the observed labeled cells are shown in dark and light gray, respectively. In the right column, diagrams summarize for each sector the hierarchical relationships that can be inferred from the observed laminar patterns of its connections. In each diagram, areas that send feedforward projections to and receive feedback projections from a given sector are indicated with white boxes in the lower part, areas displaying lateral connections are indicated with light gray boxes in the middle part, and areas that receive feedforward projections from and send feedback projections to that sector are indicated with dark gray boxes in the upper part. Abbreviations as in Figures 1 and 2.

Although several studies have already described the cortical connectivity of area 46v (Barbas and Mesulam 1985; Barbas 1988; Barbas and Pandya 1989; Preuss and Goldman-Rakic 1989; Petrides and Pandya 2002; Gerbella et al. 2010), in none of them the injection sites involved the rostral part of this area. Thus, the present data provide the first description of the cortical connectivity of this VLPF sector and robust evidence showing a rostrocaudal connectional subdivision of area 46v. Indirect evidence, agrees with the present data. First, after tracer injections in areas IPa or TEa/m (Seltzer and Pandya 1989; Saleem et al. 2008), the prefrontal labeling was mostly found to involve the rostral part of area 46v. Second, after injections in inferior or opercular parietal (e.g., Petrides and Pandya 1984; Cavada and Goldman-Rakic 1989; Neal et al. 1990; Cipolloni and Pandya 1999; Rozzi et al. 2006; Borra et al. 2008; present data), in PMv (e.g., Ghosh and Gattera 1995; Wang et al. 2002; Gerbella, Belmalih, et al. 2011), or prearcuate (e.g., Huerta et al. 1987; Stanton et al. 1993; Gerbella et al. 2010) areas, the prefrontal labeling mostly or completely involved the caudal, not the rostral, part of area 46v.

A further major finding of the present study was that the connectivity of area 46vc is topographically organized and different parts of this area are preferentially connected to different sets of parietal and PMv/prearcuate areas (see Fig. 13). Specifically, the caudal part of area 46vc shows strong connections with prearcuate areas 8/FEF, 45B, and 8r and IPL connections almost exclusively involving LIP. Indirect data from tracer injections in areas 8/FEF, 45B, 8r, and LIP (e.g., Huerta et al. 1987; Cavada and Goldman-Rakic 1989; Stanton et al. 1993; Gerbella et al. 2010) indicate that, at least based on its major cortical connections, this cortical sector is connectionally homogeneous. In contrast, the rostral part of area 46vc is robustly connected with PMv areas F5a and 44, with area SII, and with several IPL areas but LIP. Furthermore, this rostral part of area 46vc showed 2 connectionally different fields. One, located in the bank of the PS (rostral 46vc/bank), is characterized by almost equally dense connections with both PMv and IPL areas. In the PMv, these connections involve almost equally both areas F5a and 44, in the IPL almost exclusively the convexity areas PFG and PG and the adjacent opercular area PGop. The other, located on the VLPF convexity cortex (rostral 46vc/convexity), is characterized by: 1) PMv connections much denser than those with the IPL and involving F5a to a greater degree than area 44 and 2) IPL connections almost exclusively with AIP and, to a lesser extent, with area PF.

Accordingly, our data suggest that the variability in the distribution of the labeling described in other studies (Barbas and Mesulam 1985; Barbas 1988; Barbas and Pandya 1989; Preuss and Goldman-Rakic 1989; Petrides and Pandya 2002; Gerbella et al. 2010) can be accounted for by the topographic organization of the connectivity of area 46vc. Indeed, Cavada and Goldman-Rakic (1989), based on tracer injections in the IPL, first proposed a topographic organization of the parietal connectivity of area 46v. Our data from tracer injections in the IPL areas confirm and extend these observations. Specifically, after a tracer injection in the location of LIP, Cavada and Goldman-Rakic (1989) found labeling confined to the caudal part of area 46v, whereas after tracer injections in area 7a (most likely areas Opt and PG) or area 7b (likely area PFG), the labeling was located more rostrally, mostly in the bank of the PS. In this respect, it is noteworthy that in the study of these authors: 1) the labeling observed in the fundus and dorsal bank of the PS can be accounted for by the involvement of area Opt by the injection site in area 7a, as suggested by Rozzi et al. (2006) and 2) the labeling observed corresponding to rostral 46vc/convexity was relatively poor, most likely because area AIP was not fully involved by the injection sites.

Laminar Distribution of Area 46v Connections

All the various area 46v sectors identified in the present study showed laminar connectivity patterns that largely varied according to the connected regions. In general, our data show that, based on the observed patterns and on their regional distribution, the connections of the various area 46v sectors almost completely fit into the structural model of Barbas and Rempel-Clower (1997) and, to a large extent, also into the functional hierarchical model of Felleman and Van Essen (1991).

Specifically, the laminar pattern observed in lateral prefrontal and PMv/prearcuate areas (i.e., labeled cells and terminals almost equally distributed in the superficial and deep cortical layers) is the one expected in the structural model for connections between areas of similar structure and, in the functional hierarchical model, for connections between areas located at a similar hierarchical level. Though expected in lateral prefrontal areas, this pattern was also observed in dysgranular (44) and agranular (F5a) frontal areas, in spite of their lower laminar differentiation with respect to area 46v. Noteworthy, a similar pattern was also observed in area 46v after tracer injections in F5a (Gerbella, Belmalih, et al. 2011) and in area F5a after tracer injections in area 12r (Borra et al. 2011), thus suggesting that this pattern is representative of all the lateral prefrontal connections of the PMv.

Furthermore, our data on the laminar distribution of area 46v connections with orbitofrontal and cingulate areas (i.e., labeled cells and terminals mostly in the deep layers), fully replicate the observations of Barbas and Rempel-Clower (1997) on the laminar connectivity patterns of prefrontal areas on which the structural model was originally based. Noteworthy, according to Barbas and Rempel-Clower (1997), prefrontal projections terminating mostly in the deep layers (IV–VI) are comparable to the feedforward projections of sensory areas described by Felleman and Van Essen (1991).

Finally, the pattern observed in the parietal, temporal, and insular areas (i.e., labeled cells and terminals mostly in the superficial layers) is similar to that described in these areas by Rempel-Clower and Barbas (2000) and Medalla and Barbas (2006) after injections in VLPF areas. Noteworthy, according to both Barbas and Rempel-Clower (1997) and Felleman and Van Essen (1991), projections terminating mostly in superficial layers can be considered as feedback projections. Thus, the present data are in line with the notion that the prefrontal cortex has a general role in “top-down” control of behavior, for which feedback projections to higher order sensory areas are predicted (see, e.g., Miller and Cohen 2001).

Functional Considerations

The lateral prefrontal cortex is essential for executive functions and consists of several functionally distinct fields specified by different connectivity patterns (e.g., Tanji and Hoshi 2008).

Specifically, although area 46v was originally considered as part of a larger prefrontal domain involved in working memory for visuospatial information (Goldman-Rakic 1987; Levy and Goldman-Rakic 2000), several studies have shown a wider role of this area in controlling higher order aspects of behavior. Indeed, area 46v hosts neurons involved in working memory for both the identity and location of objects (Rao et al. 1997), in encoding temporal sequences of events (Ninokura et al. 2004), in learning and applying behavioral guiding rules for action selection (e.g., Hoshi et al. 1998, 2000; White and Wise 1999; Murray et al. 2000), and in controlling complex actions in terms of temporal organization (Mushiake et al. 2006; Saga et al. 2011) and final goals (Saito et al. 2005). In all these studies, the sites recorded in area 46v appear to be confined to its caudal half, in line with the notion, suggested by the present study, of a rostrocaudal subdivision of area 46v in which only area 46vc has a direct access to areas involved in motor control. The present data suggest that this role mostly relies on the integration of: 1) sensory and motor information originating from parietal and PMv/prearcuate areas and, for rostral area 46vc, higher order somatosensory information originating from SII; 2) nonspatial information originating from the caudal and intermediate area 12r (see, e.g., Levy and Goldman-Rakic 2000; Passingham et al. 2000; Tanji and Hoshi 2008); 3) information possibly related to abstract representations and categorizations of complex motor sequences originating from caudal 46d (Shima et al. 2007); and 4) higher order information originating from more rostral prefrontal areas, mostly area 46vr.

Furthermore, the present data appear to be helpful for providing an insight into the way in which area 46vc is involved in controlling different types of actions and aspects of motor control. Functional studies have shown that cells active in tasks requiring oculomotor responses (e.g., Boch and Goldberg 1989; Averbeck et al. 2006; Ichihara-Takeda and Funahashi 2007) and the execution of arm/hand responses (e.g., Requin et al. 1990; Hoshi et al. 1998, 2000) tended to be located more caudally and more rostrally in area 46vc, respectively. The present data, showing a topographic organization of the parietal and PMv/prearcuate connectivity of area 46vc, provide the anatomical basis for this functional segregation and for a modular organization in which executive functions are finalized for the control of different types of actions and aspects of motor control in different parts of area 46vc. Specifically, caudal 46vc is preferentially connected to parietal (LIP) and frontal (8/FEF, 8r, and 45B) areas forming parietofrontal circuits involved in guiding oculomotor behavior (Colby 1998). This connectivity pattern suggests an affiliation of the caudal 46vc with the oculomotor cortical network and the correspondence of this sector with the so called “prefrontal eye field (see Lynch and Tian 2006). In contrast, rostral area 46vc is preferentially connected to parietal (AIP, PG, PFG, PF, and SII) and frontal (F5a, 44) areas forming parietofrontal circuits involved in controlling arm, hand, or mouth actions and in action recognition (Rizzolatti et al. 1998; Fogassi and Luppino 2005). This connectivity pattern suggests a primary role of this sector of area 46vc in the executive control of arm, hand, and mouth actions. Furthermore, our data suggest a differential role of the convexity and bank sectors of rostral 46vc based on their differential parietal connectivity. Specifically, rostral 46vc/convexity shows an IPL connectivity primarily with the hand-related area AIP, forming a parietofrontal circuit with the PMv area F5 that is involved in visuomotor transformation for grasping (Jeannerod et al. 1995; Rizzolatti and Luppino 2001; Grafton 2010). Accordingly, it is possible that this sector of area 46vc is primarily involved in selecting, monitoring, and updating object-oriented hand actions based on behavioral goals, behavioral guiding rules, and current and memorized or working memory information on motor programs and object properties. The rostral 46vc/bank, on the other hand, primarily displays IPL connectivity with the arm-related area PG and the hand-related area PFG, which are both connected to the PMv area F5. PFG and F5 host neurons coding grasping according to the goal of the action in which it is embedded and PFG hosts neurons coding the final goal of complex actions at different levels of motor abstraction (Fogassi et al. 2005; Bonini et al. 2010, 2011). Thus, it is possible that the rostral 46vc/bank is preferentially involved in intentional action selection and in organizing motor acts into action sequences and keeping active internal representations of an individual’s motor intentions. In this respect, it is noteworthy that the rostral 46vc/bank was the only sector of area 46vc provided with substantial connections to the insular cortex, area 24, and the orbitofrontal cortex, which could be the sources of information about internal states, motivation, and rewards (Schultz 2000; Barbas 2007; Craig 2010; Lamm and Singer 2010).

The present study also showed that area 46vr shows an almost exclusive and extensive intraprefrontal connectivity that substantially involves VLPF, DLPF, and orbitofrontal areas and extraprefrontal connectivity substantially involving only area 24 and rostral inferotemporal areas. This connectivity pattern suggests a role of area 46vr in higher order aspects of the cognitive control of behavior. To our knowledge, there are no functional studies in which neural activity has been unequivocally recorded from this cortical sector. However, a recent electrophysiological study of area 46, in which recording sites possibly involved also area 46vr, reported neural activity related to the use of abstract response strategies for guiding motor behavior (Tsujimoto et al. 2011).

Finally, it is noteworthy that the rostrocaudal connectional gradients observed in the present study in area 46v are, in several aspects, similar to those observed more ventrally in the VLPF (areas 45A and 12r) in previous studies (Gerbella et al. 2010; Borra et al. 2011). Although areas 46v, 12r, and 45A differ markedly in terms of prefrontal, orbitofrontal, and temporal connectivity, caudal 46vc, area 45A, and the rostrally adjacent caudal part of area 12r show dense connections to prearcuate oculomotor areas. Furthermore, both rostral 46vc and the intermediate part of area 12r are connected to hand-related frontal and parietal areas. Finally, both area 46vr and the rostral part of area 12r show an almost exclusive intraprefrontal connectivity.

Altogether, these data provide evidence showing a general rostrocaudal organization of the macaque VLPF in which more caudal areas are differentially involved in controlling motor behavior based on external and internal information and more rostral areas are most likely involved in higher order, possibly more abstract, cognitive functions. Recent models of executive functions in the prefrontal cortex have emphasized a rostrocaudal hierarchical organization of cognitive processing in which more anterior regions are involved in progressively more abstract processing (Koechlin and Summerfield 2007). In these models, more caudal prefrontal regions are involved in the “contextual” control of motor behavior based on sensory and context-related information, whereas more rostral regions are involved in the “episodic” control of behavior, based on past events and abstract strategies (Koechlin and Summerfield 2007; Badre 2008; Botvinick 2008; Taren et al. 2011). The general rostrocaudal connectional organization of the macaque VLPF emerging from the results of the present and previous studies could represent the substrate of these models of cognitive processing in the primate prefrontal cortex.

Funding

European Research Council (Grant number: Cogsystems FP7-250013); Ministero dell’Istruzione, dell’Universita` e della Ricerca (Grant number: PRIN 2008, no 2006052343_002); Belgian Science Policy Office (Grant number: IUAP P6/29).

The 3D reconstruction software was developed by CRS4, Pula, Cagliari, Italy. Conflict of Interest: None declared.

References

Averbeck
BB
Sohn
J-W
Lee
D
Activity in prefrontal cortex during dynamic selection of action sequences
Nat Neurosci
 , 
2006
, vol. 
9
 (pg. 
276
-
282
)
Badre
D
Cognitive control, hierarchy, and the rostro–caudal organization of the frontal lobes
Trends Cogn Sci
 , 
2008
, vol. 
12
 (pg. 
193
-
200
)
Barbas
H
Anatomic organization of basoventral and mediodorsal visual recipient prefrontal regions in the rhesus monkey
J Comp Neurol
 , 
1988
, vol. 
276
 (pg. 
313
-
342
)
Barbas
H
Flow of information for emotions through temporal and orbitofrontal pathways
J Anat
 , 
2007
, vol. 
211
 (pg. 
237
-
249
)
Barbas
H
Mesulam
MM
Cortical afferent input to the principalis region of the rhesus monkey
Neuroscience
 , 
1985
, vol. 
15
 (pg. 
619
-
637
)
Barbas
H
Pandya
DN
Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey
J Comp Neurol
 , 
1989
, vol. 
286
 (pg. 
353
-
375
)
Barbas
H
Ghashghaei
HT
Rempel-Clower
N
Xiao
D
Grafman
J
Anatomic basis of functional specialization in prefrontal cortices in primates
Handbook of neuropsychology
 , 
2002
Amsterdam (The Netherlands)
Elsevier Science
(pg. 
1
-
27
)
Barbas
H
Rempel-Clower
N
Cortical structure predicts the pattern of corticocortical connections
Cereb Cortex
 , 
1997
, vol. 
7
 (pg. 
635
-
646
)
Belmalih
A
Borra
E
Contini
M
Gerbella
M
Rozzi
S
Luppino
G
Multimodal architectonic subdivision of the rostral part (area F5) of the macaque ventral premotor cortex
J Comp Neurol
 , 
2009
, vol. 
512
 (pg. 
183
-
217
)
Bettio
F
Demelio
S
Gobbetti
E
Luppino
G
Matelli
M
Interactive 3-D reconstruction and visualization of primates cerebral cortex
 , 
2001
Program No 728.4 2001 Neuroscience Meeting Planner. San Diego, CA: Society of Neuroscience
Boch
RA
Goldberg
ME
Participation of prefrontal neurons in the preparation of visually guided eye movements in the rhesus monkey
J Neurophysiol
 , 
1989
, vol. 
61
 (pg. 
1064
-
1084
)
Bonini
L
Rozzi
S
Serventi
FU
Simone
L
Ferrari
PF
Fogassi
L
Ventral premotor and inferior parietal cortices make distinct contribution to action organization and intention understanding
Cereb Cortex
 , 
2010
, vol. 
20
 (pg. 
1372
-
1385
)
Bonini
L
Ugolotti Serventi
F
Simone
L
Rozzi
S
Ferrari
PF
Fogassi
L
Grasping neurons of monkey parietal and premotor cortices encode action goals at distinct levels of abstraction during complex action sequences
J Neurosci
 , 
2011
, vol. 
31
 (pg. 
5876
-
5886
)
Borra
E
Belmalih
A
Calzavara
R
Gerbella
M
Murata
A
Rozzi
S
Luppino
G
Cortical connections of the macaque anterior intraparietal (AIP) area
Cereb Cortex
 , 
2008
, vol. 
18
 (pg. 
1094
-
1111
)
Borra
E
Gerbella
M
Rozzi
S
Luppino
G
Anatomical evidence for the involvement of the macaque ventrolateral prefrontal area 12r in controlling goal-directed actions
J Neurosci
 , 
2011
, vol. 
31
 (pg. 
12351
-
12363
)
Botvinick
M
Hierarchical models of behavior and prefrontal function
Trends Cogn Sci
 , 
2008
, vol. 
12
 (pg. 
201
-
208
)
Carmichael
ST
Price
JL
Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey
J Comp Neurol
 , 
1994
, vol. 
346
 (pg. 
366
-
402
)
Cavada
C
Goldman-Rakic
PS
Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe
J Comp Neurol
 , 
1989
, vol. 
287
 (pg. 
422
-
445
)
Cipolloni
PB
Pandya
DN
Cortical connections of the frontoparietal opercular areas in the rhesus monkey
J Comp Neurol
 , 
1999
, vol. 
403
 (pg. 
431
-
458
)
Colby
CL
Action-oriented spatial reference frames in cortex
Neuron
 , 
1998
, vol. 
20
 (pg. 
15
-
24
)
Craig
A
The sentient self
Brain Struct Funct
 , 
2010
, vol. 
214
 (pg. 
563
-
577
)
Felleman
DJ
Van Essen
DC
Distributed hierarchical processing in primate cerebral cortex
Cereb Cortex
 , 
1991
, vol. 
1
 (pg. 
1
-
47
)
Fitzgerald
PJ
Lane
JW
Thakur
PH
Hsiao
SS
Receptive field properties of the macaque second somatosensory cortex: evidence for multiple functional representations
J Neurosci
 , 
2004
, vol. 
24
 (pg. 
11193
-
11204
)
Fogassi
L
Ferrari
PF
Gesierich
B
Rozzi
S
Chersi
F
Rizzolatti
G
Parietal lobe: from action organization to intention understanding
Science
 , 
2005
, vol. 
308
 (pg. 
662
-
667
)
Fogassi
L
Luppino
G
Motor functions of the parietal lobe
Curr Opin Neurobiol
 , 
2005
, vol. 
15
 (pg. 
626
-
631
)
Gerbella
M
Belmalih
A
Borra
E
Rozzi
S
Luppino
G
Multimodal architectonic subdivision of the caudal ventrolateral prefrontal cortex of the macaque monkey
Brain Struct Funct
 , 
2007
, vol. 
212
 (pg. 
269
-
301
)
Gerbella
M
Belmalih
A
Borra
E
Rozzi
S
Luppino
G
Cortical connections of the macaque caudal ventrolateral prefrontal areas 45A and 45B
Cereb Cortex
 , 
2010
, vol. 
20
 (pg. 
141
-
168
)
Gerbella
M
Belmalih
A
Borra
E
Rozzi
S
Luppino
G
Cortical connections of the anterior (F5a) subdivision of the macaque ventral premotor area F5
Brain Struct Funct
 , 
2011
, vol. 
216
 (pg. 
43
-
65
)
Gerbella
M
Borra
E
Rozzi
S
Tonelli
S
Luppino
G
Topographic organization of the parietal connections of the macaque ventral area 46 Program No 91410 2011 Neuroscience Meeting Planner
 , 
2011
Washington (DC)
Society for Neuroscience
Ghosh
S
Gattera
R
A comparison of the ipsilateral cortical projections to the dorsal and ventral subdivisions of the macaque premotor cortex
Somatosens Mot Res
 , 
1995
, vol. 
12
 (pg. 
359
-
378
)
Goldman-Rakic
P
Plum
F
Mountcastle
F
Circuitry of primate prefrontal cortex and regulation of behavior by representational memory
Handbook of physiology
 , 
1987
Washington (DC)
The American Physiological Society
(pg. 
373
-
515
)
Grafton
ST
The cognitive neuroscience of prehension: recent developments
Exp Brain Res
 , 
2010
, vol. 
204
 (pg. 
475
-
491
)
Gregoriou
GG
Borra
E
Matelli
M
Luppino
G
Architectonic organization of the inferior parietal convexity of the macaque monkey
J Comp Neurol
 , 
2006
, vol. 
496
 (pg. 
422
-
451
)
Hoshi
E
Shima
K
Tanji
J
Task-dependent selectivity of movement-related neuronal activity in the primate prefrontal cortex
J Neurophysiol
 , 
1998
, vol. 
80
 (pg. 
3392
-
3397
)
Hoshi
E
Shima
K
Tanji
J
Neuronal activity in the primate prefrontal cortex in the process of motor selection based on two behavioral rules
J Neurophysiol
 , 
2000
, vol. 
83
 (pg. 
2355
-
2373
)
Huerta
MF
Krubitzer
LA
Kaas
JH
Frontal eye field as defined by intracortical microstimulation in squirrel monkeys, owl monkeys, and macaque monkeys II. Cortical connections
J Comp Neurol
 , 
1987
, vol. 
265
 (pg. 
332
-
361
)
Ichihara-Takeda
S
Funahashi
S
Activity of primate orbitofrontal and dorsolateral prefrontal neurons: task-related activity during an oculomotor delayed-response task
Exp Brain Res
 , 
2007
, vol. 
181
 (pg. 
409
-
425
)
Jeannerod
M
Arbib
MA
Rizzolatti
G
Sakata
H
Grasping objects: the cortical mechanisms of visuomotor transformation
Trends Neurosci
 , 
1995
, vol. 
18
 (pg. 
314
-
320
)
Koechlin
E
Summerfield
C
An information theoretical approach to prefrontal executive function
Trends Cogn Sci
 , 
2007
, vol. 
11
 (pg. 
229
-
235
)
Lamm
C
Singer
T
The role of anterior insular cortex in social emotions
Brain Struct Funct
 , 
2010
, vol. 
214
 (pg. 
579
-
591
)
Levy
R
Goldman-Rakic
PS
Segregation of working memory functions within the dorsolateral prefrontal cortex
Exp Brain Res
 , 
2000
, vol. 
133
 (pg. 
23
-
32
)
Luppino
G
Calzavara
R
Rozzi
S
Matelli
M
Projections from the superior temporal sulcus to the agranular frontal cortex in the macaque
Eur J Neurosci
 , 
2001
, vol. 
14
 (pg. 
1035
-
1040
)
Luppino
G
Murata
A
Govoni
P
Matelli
M
Largely segregated parietofrontal connections linking rostral intraparietal cortex (areas AIP and VIP) and the ventral premotor cortex (areas F5 and F4)
Exp Brain Res
 , 
1999
, vol. 
128
 (pg. 
181
-
187
)
Luppino
G
Rozzi
S
Calzavara
R
Matelli
M
Prefrontal and agranular cingulate projections to the dorsal premotor areas F2 and F7 in the macaque monkey
Eur J Neurosci
 , 
2003
, vol. 
17
 (pg. 
559
-
578
)
Lynch
JC
Tian
JR
Cortico-cortical networks and cortico-subcortical loops for the higher control of eye movements
Prog Brain Res
 , 
2006
, vol. 
151
 (pg. 
461
-
501
)
Matelli
M
Govoni
P
Galletti
C
Kutz
DF
Luppino
G
Superior area 6 afferents from the superior parietal lobule in the macaque monkey
J Comp Neurol
 , 
1998
, vol. 
402
 (pg. 
327
-
352
)
Matelli
M
Luppino
G
Rizzolatti
G
Patterns of cytochrome oxidase activity in the frontal agranular cortex of macaque monkey
Behav Brain Res
 , 
1985
, vol. 
18
 (pg. 
125
-
137
)
Matelli
M
Luppino
G
Rizzolatti
G
Architecture of superior and mesial area 6 and the adjacent cingulate cortex in the macaque monkey
J Comp Neurol
 , 
1991
, vol. 
311
 (pg. 
445
-
462
)
Medalla
M
Barbas
H
Diversity of laminar connections linking periarcuate and lateral intraparietal areas depends on cortical structure
Eur J Neurosci
 , 
2006
, vol. 
23
 (pg. 
161
-
179
)
Mesulam
M-M
Mesulam
M-M
Principles of horseradish peroxidase neurohistochemistry and their applications for tracing neural pathways
Tracing neural connections with horseradish peroxidase
 , 
1982
Chichester (UK)
Wiley
(pg. 
1
-
152
)
Mesulam
MM
Mufson
EJ
Insula of the old world monkey. Architectonics in the insulo-orbito-temporal component of the paralimbic brain
J Comp Neurol
 , 
1982
, vol. 
212
 (pg. 
1
-
22
)
Miller
EK
Cohen
JD
An integrative theory of prefrontal cortex function
Ann Rev Neurosci
 , 
2001
, vol. 
24
 (pg. 
167
-
202
)
Murray
EA
Bussey
TJ
Wise
SP
Role of prefrontal cortex in a network for arbitrary visuomotor mapping
Exp Brain Res
 , 
2000
, vol. 
133
 (pg. 
114
-
129
)
Mushiake
H
Saito
N
Sakamoto
K
Itoyama
Y
Tanji
J
Activity in the lateral prefrontal cortex reflects multiple steps of future events in action plans
Neuron
 , 
2006
, vol. 
50
 pg. 
631
 
Neal
JW
Pearson
RC
Powell
TP
The ipsilateral corticocortical connections of area 7 with the frontal lobe in the monkey
Brain Res
 , 
1990
, vol. 
509
 (pg. 
31
-
40
)
Ninokura
Y
Mushiake
H
Tanji
J
Integration of temporal order and object information in the monkey lateral prefrontal cortex
J Neurophysiol
 , 
2004
, vol. 
91
 (pg. 
555
-
560
)
Pandya
DN
Seltzer
B
Intrinsic connections and architectonics of posterior parietal cortex in the rhesus monkey
J Comp Neurol
 , 
1982
, vol. 
204
 (pg. 
196
-
210
)
Passingham
RE
Toni
I
Rushworth
MFS
Specialisation within the prefrontal cortex: the ventral prefrontal cortex and associative learning
Exp Brain Res
 , 
2000
, vol. 
133
 (pg. 
103
-
113
)
Petrides
M
Pandya
DN
Projections to the frontal cortex from the posterior parietal region in the rhesus monkey
J Comp Neurol
 , 
1984
, vol. 
228
 (pg. 
105
-
116
)
Petrides
M
Pandya
DN
Boller
F
Grafman
J
Comparative architectonic analysis of the human and the macaque frontal cortex
Handbook of neuropsychology
 , 
1994
Amsterdam (The Netherlands)
Elsevier
(pg. 
17
-
58
)
Petrides
M
Pandya
DN
Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey
Eur J Neurosci
 , 
2002
, vol. 
16
 (pg. 
291
-
310
)
Preuss
TM
Goldman-Rakic
PS
Connections of the ventral granular frontal cortex of macaques with perisylvian premotor and somatosensory areas: anatomical evidence for somatic representation in primate frontal association cortex
J Comp Neurol
 , 
1989
, vol. 
282
 (pg. 
293
-
316
)
Preuss
TM
Goldman-Rakic
PS
Myelo- and cytoarchitecture of the granular frontal cortex and surrounding regions in the streptisine primate Galago and the anthropoid primate Macaca
J Comp Neurol
 , 
1991
, vol. 
310
 (pg. 
429
-
474
)
Rao
SC
Rainer
G
Miller
EK
Integration of what and where in the primate prefrontal cortex
Science
 , 
1997
, vol. 
276
 (pg. 
821
-
824
)
Rempel-Clower
NL
Barbas
H
The laminar pattern of connections between prefrontal and anterior temporal cortices in the rhesus monkey is related to cortical structure and function
Cereb Cortex
 , 
2000
, vol. 
10
 (pg. 
851
-
865
)
Requin
J
Lecas
J-C
Vitton
N
A comparison of preparation-related neuronal activity changes in the prefrontal, premotor, primary motor and posterior parietal areas of the monkey cortex: preliminary results
Neurosci Lett
 , 
1990
, vol. 
111
 (pg. 
151
-
156
)
Rizzolatti
G
Luppino
G
The cortical motor system
Neuron
 , 
2001
, vol. 
31
 (pg. 
889
-
901
)
Rizzolatti
G
Luppino
G
Matelli
M
The organization of the cortical motor system: new concepts
Electroencephalogr Clin Neurophysiol
 , 
1998
, vol. 
106
 (pg. 
283
-
296
)
Rozzi
S
Calzavara
R
Belmalih
A
Borra
E
Gregoriou
GG
Matelli
M
Luppino
G
Cortical connections of the inferior parietal cortical convexity of the macaque monkey
Cereb Cortex
 , 
2006
, vol. 
16
 (pg. 
1389
-
1417
)
Saga
Y
Iba
M
Tanji
J
Hoshi
E
Development of multidimensional representations of task phases in the lateral prefrontal cortex
J Neurosci
 , 
2011
, vol. 
31
 (pg. 
10648
-
10665
)
Saito
N
Mushiake
H
Sakamoto
K
Itoyama
Y
Tanji
J
Representation of immediate and final behavioral goals in the monkey prefrontal cortex during an instructed delay period
Cereb Cortex
 , 
2005
, vol. 
15
 (pg. 
1535
-
1546
)
Saleem
KS
Kondo
K
Price
JL
Complementary circuits connecting the orbital and medial prefrontal networks with the temporal, insular, and opercular cortex in the macaque monkey
J Comp Neurol
 , 
2008
, vol. 
506
 (pg. 
659
-
693
)
Schlag
J
Schlag-Rey
M
Evidence for a supplementary eye field
J Neurophysiol
 , 
1987
, vol. 
57
 (pg. 
179
-
200
)
Schultz
W
Multiple reward signals in the brain
Nat Rev Neurosci
 , 
2000
, vol. 
1
 (pg. 
199
-
207
)
Seltzer
B
Pandya
DN
Afferent cortical connections and architectonics of the superior temporal sulcus and surrounding cortex in the rhesus monkey
Brain Res
 , 
1978
, vol. 
149
 (pg. 
1
-
24
)
Seltzer
B
Pandya
DN
Frontal lobe connections of the superior temporal sulcus in the rhesus monkey
J Comp Neurol
 , 
1989
, vol. 
281
 (pg. 
97
-
113
)
Shima
K
Isoda
M
Mushiake
H
Tanji
J
Categorization of behavioural sequences in the prefrontal cortex
Nature
 , 
2007
, vol. 
445
 (pg. 
315
-
318
)
Stanton
GB
Bruce
CJ
Goldberg
ME
Topography of projections to the frontal lobe from the macaque frontal eye fields
J Comp Neurol
 , 
1993
, vol. 
330
 (pg. 
286
-
301
)
Tanji
J
Hoshi
E
Role of the lateral prefrontal cortex in executive behavioral control
Physiol Rev
 , 
2008
, vol. 
88
 (pg. 
37
-
57
)
Taren
AA
Venkatraman
V
Huettel
SA
A parallel functional topography between medial and lateral prefrontal cortex: evidence and implications for cognitive control
J Neurosci
 , 
2011
, vol. 
31
 (pg. 
5026
-
5031
)
Tsujimoto
S
Genovesio
A
Wise
SP
Comparison of strategy signals in the dorsolateral and orbital prefrontal cortex
J Neurosci
 , 
2011
, vol. 
31
 (pg. 
4583
-
4592
)
Walker
E
A cytoarchitectural study of the prefrontal area of the macaque monkey
J Comp Neurol
 , 
1940
, vol. 
98
 (pg. 
59
-
86
)
Wang
Y
Shima
K
Isoda
M
Sawamura
H
Tanji
J
Spatial distribution and density of prefrontal cortical cells projecting to three sectors of the premotor cortex
Neuroreport
 , 
2002
, vol. 
13
 (pg. 
1341
-
1344
)
White
IM
Wise
SP
Rule-dependent neuronal activity in the prefrontal cortex
Exp Brain Res
 , 
1999
, vol. 
126
 (pg. 
315
-
335
)