Elsevier

NeuroImage

Volume 93, Part 2, June 2014, Pages 260-275
NeuroImage

Full Length Article
Cytoarchitecture, probability maps and functions of the human frontal pole

https://doi.org/10.1016/j.neuroimage.2013.05.052Get rights and content

Highlights

  • The human frontopolar cortex consists of two cytoarchitectonically distinct areas.

  • 3D probabilistic maps of frontopolar area 1 and 2 (Fp1,Fp2) were created.

  • Quantitative inference showed involvement in cognition (Fp1) and emotion (Fp2).

  • Significant difference in task-based functional connectivity between Fp1 and Fp2.

Abstract

The frontal pole has more expanded than any other part in the human brain as compared to our ancestors. It plays an important role for specifically human behavior and cognitive abilities, e.g. action selection (Kovach et al., 2012). Evidence about divergent functions of its medial and lateral part has been provided, both in the healthy brain and in psychiatric disorders. The anatomical correlates of such functional segregation, however, are still unknown due to a lack of stereotaxic, microstructural maps obtained in a representative sample of brains. Here we show that the human frontopolar cortex consists of two cytoarchitectonically and functionally distinct areas: lateral frontopolar area 1 (Fp1) and medial frontopolar area 2 (Fp2). Based on observer-independent mapping in serial, cell-body stained sections of 10 brains, three-dimensional, probabilistic maps of areas Fp1 and Fp2 were created. They show, for each position of the reference space, the probability with which each area was found in a particular voxel. Applying these maps as seed regions for a meta-analysis revealed that Fp1 and Fp2 differentially contribute to functional networks: Fp1 was involved in cognition, working memory and perception, whereas Fp2 was part of brain networks underlying affective processing and social cognition. The present study thus disclosed cortical correlates of a functional segregation of the human frontopolar cortex. The probabilistic maps provide a sound anatomical basis for interpreting neuroimaging data in the living human brain, and open new perspectives for analyzing structure–function relationships in the prefrontal cortex. The new data will also serve as a starting point for further comparative studies between human and non-human primate brains. This allows finding similarities and differences in the organizational principles of the frontal lobe during evolution as neurobiological basis for our behavior and cognitive abilities.

Introduction

Brodmann area (BA) 10 is located at the frontal pole of the human brain and represents the most rostral part of the brain. It is part of the prefrontal cortex (PFC). Its large extent in the human brain as compared to other species (Semendeferi et al., 2001) makes it a candidate for processing “human-specific” functions. BA10 is involved in many higher cognitive functions such as planning of future actions and the ability to draw analogies (Fuster, 2008). There are several theories (reviewed by e.g. Ramnani and Owen (2004) or Tsujimoto et al. (2011)), like the gateway hypotheses (Burgess et al., 2005, Burgess et al., 2007) or the hypotheses of cognitive branching (Koechlin et al., 1999) which try to combine the variety of neuroimaging findings.

The precise localization of the borders of BA10 using structural or functional MRI is not possible. In contrast to the primary sensory areas with their distinct cyto- and myeloarchitecture (Zilles and Amunts, 2010, Zilles and Amunts, 2012), the relatively similar architecture of the various six-layered isocortical areas of the prefrontal cortex does not provide sufficient tissue contrast for in vivo mapping of such subtle differences. In vivo mapping approaches, which predict the localization of areal borders by cortical folding patterns work well in primary cortical areas, but are less successful in higher associative areas (Fischl et al., 2008, Fischl et al., 2009, Hinds et al., 2008, Hinds et al., 2009). Using high-field MRI and the myelin-based contrast allowed delineating the primary visual cortex (Geyer et al., 2011), but a definition of borders of higher associative cortical areas and higher sensory areas like that on the human frontal pole could not be demonstrated until now. Such MR-derived myelin maps are impaired in regions close to air/tissue interfaces, like the orbitofrontal cortex and the frontal pole adjacent to the frontal sinus (Glasser and Van Essen, 2011) because of susceptibility artifacts. Delineating cortical regions based on connectivity patterns taken from diffusion weighted MRI in living subjects is another in vivo option which might lead to localization of higher order cortical areas, but this approach requires reliably and precisely defined regions of interest for fiber tracking (Behrens and Johansen-Berg, 2005, Johansen-Berg et al., 2004). In the vast majority of areas, the delineation of cytoarchitectonic areas of the isocortex provides presently the only precise, reliable and reproducible basis for anatomical localization of functional studies and independent evaluation of structural in vivo mapping approaches.

The cytoarchitectonic map of Korbinian Brodmann (Brodmann, 1909) (Fig. 1A) shows an area BA10, occupying the frontal pole including the frontomarginal sulcus, the rostral part of the superior frontal gyrus and small parts of the middle frontal gyrus. Caudally, BA10 is bordered by middle frontal area BA46. The mesial border to BA32 is located rostral to the cingulate gyrus. The rostral end of the olfactory sulcus could be taken as a gross macroscopic landmark for the borderline to orbitofrontal area BA11 according to Brodmann's map. A comparable cytoarchitectonic map (Fig. 1B) was proposed by (von Economo and Koskinas (1925) and Sarkisov and the Russian school (Fig. 1C) (Sarkisov et al., 1949).

In a more recently published map (Öngür et al., 2003), area 10 is subdivided into three parts, 10 m, 10r, and 10p (Fig. 1D). Area 10p occupies the frontal pole, while 10 m and 10r are found on the lower part of the mesial surface of the frontal lobe. The map of Öngür and colleagues differs from the older maps by the larger extent of area 10 on the mesial surface of the brain. It shows 10 m and 10r as a broad “tongue” extending on the most ventral part of the cingulate gyrus.

Thus, the parcellations of area 10 provided by these maps differ regarding the number of subdivisions as well as the extent of the areas. This might reflect interindividual anatomical variability of the extent, and different parcellations methods and concepts in case of the number of subdivisions. The interindividual variability is an important aspect of cytoarchitectonic parcellations as shown by the probability maps of different cortical regions, e.g. various visual areas (Amunts et al., 2000, Malikovic et al., 2007), primary motor cortex (Geyer et al., 1996), primary and secondary somatosensory cortices (Eickhoff et al., 2006a, Eickhoff et al., 2006b, Geyer et al., 1999, Geyer et al., 2000, Grefkes et al., 2001), Broca's region (Amunts et al., 1999), primary auditory cortex (Morosan et al., 2001), and parietal cortex (Caspers et al., 2006, Eickhoff et al., 2006a). These factors influencing cortical parcellation schemes have been discussed elsewhere (Zilles and Amunts, 2010).

Furthermore, existing maps of the frontal pole have not been published in a format, which enables comparisons with functional imaging data in a common spatial reference system. This is important, because recent functional studies showed different activations for the lateral and medial part of the frontal pole (Burgess et al., 2003, Gilbert et al., 2007, Gilbert et al., 2010, Schilbach et al., 2010).

The aim of the present study was to investigate if the functional differentiation into a medial and lateral region within area 10 is reflected by cytoarchitecture, and to generate three-dimensional, probabilistic maps. The borders of cytoarchitectonic areas were delineated in serial histological sections of 10 postmortem brains using an observer-independent approach (Schleicher et al., 1999, Schleicher et al., 2000, Schleicher et al., 2005, Schleicher et al., 2009). Two new areas, Fp1 and Fp2, were found by quantitative cytoarchitectonic criteria, and probability maps were generated in a standard reference space, which capture the intersubject variability in localization and extent, and provide a common reference system for comparison with functional imaging data. In order to better understand the functional role of the two identified areas, these new cytoarchitectonic maps served as regions of interest for a consecutive coordinate-based meta-analysis.

Section snippets

Histological processing of postmortem brains

Ten brains, 5 females and 5 males, were obtained via the body donor program of the Department of Anatomy at the University of Düsseldorf, Germany (Table 1). Postmortem delay of brain extraction ranged between 8 and 13 h. Clinical records did not show neurological or psychiatric diseases. Written informed consent was obtained according to the body donor program by the University of Düsseldorf governed by the local ethics committee. Histological processing has been performed as previously

General characteristics

Areas Fp1 and Fp2 represent typical isocortical areas with six layers. The border between layers II and III was clear cut (Fig. 4). Layer II consisted of a high amount of granular cells, which were intermingled by pyramidal cells of very small size from layer III. Consequently, the impression of a well demarcated border to layer III was mainly caused by the much lower cell density in upper layer III as compared to layer II. Layer III showed a gradient in pyramidal cell size from superficial

Discussion

The present study entailed a three-dimensional, cytoarchitectonic map of the human frontal pole, which considers its interindividual variability. It is based on observer-independently detected borders and is available in the MNI reference space, where it can be directly compared to results of functional imaging studies. BA10 has been subdivided into two cytoarchitectonically distinct areas: area Fp1 located laterally and Fp2 located medially. The cytoarchitectonic-based map was used for a

Acknowledgments

This study was supported by the BMBF (01GW0612, K.A.). Further funding was granted by the Helmholtz Alliance for Mental Health in an Aging Society (HelMA; K.A., K.Z.) and by the Helmholtz Alliance on Systems Biology (Human Brain Model; K.Z., S.B.E.). The authors thank Katerina Semendeferi for critical review of the manuscript and for helpful discussions.

Conflict of interest

The authors declare that there is no conflict of interest.

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