Cytoarchitecture, intersubject variability, and 3D mapping of four new areas of the human anterior prefrontal cortex

Abstract

The dorsolateral prefrontal cortex (DLPFC) plays a key role in cognitive control and executive functions, including working memory, attention, value encoding, decision making, monitoring, and controlling behavioral strategies. However, the relationships between this variety of functions and the underlying cortical areas, which specifically contribute to these functions, are not yet well-understood. Existing microstructural maps differ in the number, localization, and extent of areas of the DLPFC. Moreover, there is a considerable intersubject variability both in the sulcal pattern and in the microstructure of this region, which impedes comparison with functional neuroimaging studies. The aim of this study was to provide microstructural, cytoarchitectonic maps of the human anterior DLPFC in 3D space. Therefore, we analyzed 10 human post-mortem brains and mapped their borders using a well-established approach based on statistical image analysis. Four new areas (i.e., SFS1, SFS2, MFG1, and MFG2) were identified in serial, cell-body stained brain sections that occupy the anterior superior frontal sulcus and middle frontal gyrus, i.e., a region corresponding to parts of Brodmann areas 9 and 46. Differences between areas in cytoarchitecture were captured using gray level index profiles, reflecting changes in the volume fraction of cell bodies from the surface of the brain to the cortex-white matter border. A hierarchical cluster analysis of these profiles indicated that areas of the anterior DLPFC displayed higher cytoarchitectonic similarity between each other than to areas of the neighboring frontal pole (areas Fp1 and Fp2), Broca's region (areas 44 and 45) of the ventral prefrontal cortex, and posterior DLPFC areas (8d1, 8d2, 8v1, and 8v2). Area-specific, cytoarchitectonic differences were found between the brains of males and females. The individual areas were 3D-reconstructed, and probability maps were created in the MNI Colin27 and ICBM152casym reference spaces to take the variability of areas in stereotaxic space into account. The new maps contribute to Julich-Brain and are publicly available as a resource for studying neuroimaging data, helping to clarify the functional and organizational principles of the human prefrontal cortex.

New organizational principles and 3D cytoarchitectonic maps of the dorsolateral prefrontal cortex in the human brain

“…In the anterior parts of the DLPFC, newly delineated areas share borders with previously mapped areas, like SFS1 and SFS2 (Bruno et al, 2022 ). Compared to area SFG4, area SFS1 showed a homogenous appearance as the layers were composed of equally sized cells without larger pyramidal neurons in layers III or V ( Figure 5F ).…”

“…Hierarchical cluster analysis was performed to detect similarities between the new DLPFC areas and the neighboring frontal pole areas (Fp1, Fp2) (Bludau et al, 2014 ), anterior DLPFC areas (Bruno et al, 2022 ), areas 44 and 45 of Broca's region (Amunts et al, 1999 ), subdivisions of areas 8 [8d1, 8d2, 8v1, and 8v2 (Amunts et al, 2021 )] and areas of the motoric region, like 6d1, 6d2, and 6d3 (Amunts et al, 2021 ), and 4a, and 4p (Geyer et al, 1996 ). Three sections with an average of 15–20 profiles per hemisphere were extracted for each area and brain, i.e., approximately 45 profiles per hemisphere (900 profiles total).…”

“…At the macroscopic level, refined parcellations of the human cortex from MRI-based studies (Goulas et al, 2012 ; Cieslik et al, 2013 ; Sallet et al, 2013 ; Glasser et al, 2016 ; Donahue et al, 2018 ) were published. However, segmentation of human DLPFC is challenging due to the interindividual variation in sulcus patterns (Vogt and Vogt, 1926 ; Ono et al, 1990 ; Huttner, 2004 ; Miller et al, 2021 ; Bruno et al, 2022 ; Willbrand et al, 2023 ). At the microscopic level, there is a lack of information in three-dimensional (3D) space, which does not allow a direct superimposition of previous maps with datasets from functional imaging studies (Zilles and Amunts, 2010 ).…”

“…Starting from this work, the present study aimed to analyze remaining parts of the DLPFC to understand the DLPFC better and provide a microstructural reference for functional studies. These mainly include regions on the sfg and mfg as well as the adjoining sulci bordering already delineated areas such as frontal pole area Fp1 (Bludau et al, 2014 ), the premotor area 6d3 (Sigl, 2018 ), subdivision of area 8 (8d1, 8d2, 8v1, and 8v2) (Amunts et al, 2021 ), anterior DLPFC areas (SFS1, SFS2, MFG1, and MFG2) (Bruno et al, 2022 ), areas of the Broca region (44 and 45) of the ventral lateral prefrontal cortex (VLPFC) (Amunts et al, 1999 ), and areas ifs1 and ifs3 in the inferior frontal sulcus ( ifs ) (Ruland et al, 2022 ). To address the interindividual variability of the DLPFC, probabilistic maps will be generated for each identified area in two common stereotaxic spaces (Amunts et al, 2020 ) to provide a reference system for future complementary functional and multimodal approaches.…”

Neuroanatomical and functional dissociations between variably present anterior lateral prefrontal sulci

“…Given our prior work revealing better reasoning performance overall among participants with a left, but not right, pimfs-v (Willbrand, Jackson, et al, 2023;, future work should assess whether the incidence of this sulcal component relates to activation of RLPFC-and whether this mediates the behavioral difference seen between individuals who do or do not possess a left pimfs-v component. Further, once improved cytoarchitectural definitions fully characterize the aMFG (Amunts et al, 2020;Bludau et al, 2014;Bruno et al, 2022;Wojtasik et al, 2020), future investigations could relate the presence/absence of the pimfs components to shifts in cytoarchitectonic regions (Figure 5D), given previous findings for sulcal variations in medial PFC (Amiez et al, 2021).…”