Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe
Curation statements for this article:-
Curated by eLife
eLife assessment
Rapan et al. report a new multi-modal parcellation of the macaque frontal cortex based on cytoarchitectural division complemented with functional connectivity and neurochemical data. This builds on prior highly influential maps that subdivide the cortex based on anatomical fingerprints, both confirming these prior reports and defining new subdivisions. As such, this is a fundamental contribution with compelling results that can guide future neuroscientific research into the function of the frontal lobes.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Neuroscience (eLife)
Abstract
Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker’s areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α 2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.
Article activity feed
-
-
Author Response
Reviewer #1 (Public Review):
Rapan et al. analyzed the cytoarchitectonic of the prefrontal cortex based on observer-independent analysis, confirming previous parcellations based on cyto-, myelo-, and immunoarchitectonic approaches, but also defining novel subdivisions of areas 10, 9, 8B, and 46 and identified the receptor density "fingerprint" of each area and subdivision. Furthermore, they analyzed the functional connectivity of the prefrontal cortex with caudal frontal, cingulate, parietal, and occipital areas to identify specific features for the various prefrontal subdivisions. Altogether, this study corroborates previous parcellations of the prefrontal cortex, adds new cortical subdivisions, and provides a neurochemical description of the prefrontal areas useful for comparative considerations and for guiding …
Author Response
Reviewer #1 (Public Review):
Rapan et al. analyzed the cytoarchitectonic of the prefrontal cortex based on observer-independent analysis, confirming previous parcellations based on cyto-, myelo-, and immunoarchitectonic approaches, but also defining novel subdivisions of areas 10, 9, 8B, and 46 and identified the receptor density "fingerprint" of each area and subdivision. Furthermore, they analyzed the functional connectivity of the prefrontal cortex with caudal frontal, cingulate, parietal, and occipital areas to identify specific features for the various prefrontal subdivisions. Altogether, this study corroborates previous parcellations of the prefrontal cortex, adds new cortical subdivisions, and provides a neurochemical description of the prefrontal areas useful for comparative considerations and for guiding functional and clinical studies.
Strengths:
- This study provides a detailed cytoarchitectonic map of the prefrontal cortex enriched with receptor density and functional connectivity data.
- The authors shared the data via repositories and applied their map to a macaque MRI atlas to further facilitate data sharing.
Weaknesses:
- The temporal cortex should be included in the functional connectivity analysis as it is known from anatomical studies that most prefrontal areas display rich connectivity with temporal areas. The aim of creating a comprehensive view of the frontal cortex makes the manuscript data-rich but cursory in discussing the relevant anatomical and functional literature.
One of the main concerns pointed out by reviewers was that the functional connectivity analysis is incomplete without temporal lobe areas. Although our initial decision was to use only our parcellation scheme, we fully agree with reviewers. Thus, we have extended our functional connectivity analysis, and combined our frontal, parietal, cingulate and occipital parcellations with temporal areas as defined in the atlas of Kennedy and colleagues (Markov et al., 2014). In the revised version of the manuscript, old Figures 13-17, and related Supplementary Figures 12 and 13, have been replaced with new Figures 12-15 and Figures 12-15 – Figure supplements 12, 13 and 14, and the results are described in the updated Results, chapter 3.4 Functional connectivity analysis. The Discussion has also been adjusted regarding the updated results.
Reviewer #2 (Public Review):
Rapan and colleagues did perform an impressive multi-modal parcellation of the macaque frontal cortex. In addition to qualitative cytoarchitectonic and resting-state functional fMRI data analyses, the authors based their parcellation on quantitative receptor density analysis of 14 receptors. Compared with the classic Walker map of the macaque frontal cortex, the authors produced a more refined map. Those results should be discussed in light of previous work on the same topic (Petrides et al. 2012 Cortex; Reveley et al. 2017 Cerebral Cortex; Saleem and Logothetis 2012).
In the Discussion, under chapter “4.1 Comparison with previous architectonic maps of macaque prefrontal region” (pages 44-52), we compared our parcellation to previously published maps, including the work of Petrides and colleagues (i.e., Petrides and Pandya 1984, 1994, 1999,2002, 2006, 2009; Petrides 2000, 2005; Petrides et al. 2012). With the exception of Caminiti et al. (2017), which integrates work by Belmalih et al. (2009); Borra et al. (2011, 2019) and Gerbella et al. (2010, 2013), we had restricted our citations to original mapping studies because we find it is important to discuss their reliability and objectivity, since they have been widely used in tracer-tract and neuroimaging studies, as well as the parcellation maps depicted in 3D atlases. Indeed, Saleem and Logothetis (Saleem & Logothetis, 2012) use the maps of Carmichael and Price (1994), Petrides and Pandya (1999, 2002) Petrides (2005) and Preuss and Goldman-Rakic (1991) for the parcellation of the prefrontal cortex in their atlas, and Reveley et al. (Reveley et al., 2017) use the map of Saleem and Logothetis (2012) in their 3D atlas. We now provide this information in the Introduction (lines 126-132):
“In recent years, several digital macaque atlases have been created (Bezgin et al., 2012; Frey et al., 2011; McLaren et al., 2009; Moirano et al., 2019; Reveley et al., 2017; Van Essen et al., 2012) based on the previous parcellations. Indeed, maps of Carmichael and Price (1994), Petrides and Pandya (1999, 2002), Petrides (2005) and Preuss and Goldman-Rakic (1991), used in atlas of Saleem and Logothetis (2012), have been brought into stereotaxic space by Reveley et al. (2017).”
-
eLife assessment
Rapan et al. report a new multi-modal parcellation of the macaque frontal cortex based on cytoarchitectural division complemented with functional connectivity and neurochemical data. This builds on prior highly influential maps that subdivide the cortex based on anatomical fingerprints, both confirming these prior reports and defining new subdivisions. As such, this is a fundamental contribution with compelling results that can guide future neuroscientific research into the function of the frontal lobes.
-
Reviewer #1 (Public Review):
Rapan et al. analyzed the cytoarchitectonic of the prefrontal cortex based on observer-independent analysis, confirming previous parcellations based on cyto-, myelo-, and immunoarchitectonic approaches, but also defining novel subdivisions of areas 10, 9, 8B, and 46 and identified the receptor density "fingerprint" of each area and subdivision. Furthermore, they analyzed the functional connectivity of the prefrontal cortex with caudal frontal, cingulate, parietal, and occipital areas to identify specific features for the various prefrontal subdivisions. Altogether, this study corroborates previous parcellations of the prefrontal cortex, adds new cortical subdivisions, and provides a neurochemical description of the prefrontal areas useful for comparative considerations and for guiding functional and clinical …
Reviewer #1 (Public Review):
Rapan et al. analyzed the cytoarchitectonic of the prefrontal cortex based on observer-independent analysis, confirming previous parcellations based on cyto-, myelo-, and immunoarchitectonic approaches, but also defining novel subdivisions of areas 10, 9, 8B, and 46 and identified the receptor density "fingerprint" of each area and subdivision. Furthermore, they analyzed the functional connectivity of the prefrontal cortex with caudal frontal, cingulate, parietal, and occipital areas to identify specific features for the various prefrontal subdivisions. Altogether, this study corroborates previous parcellations of the prefrontal cortex, adds new cortical subdivisions, and provides a neurochemical description of the prefrontal areas useful for comparative considerations and for guiding functional and clinical studies.
Strengths:
- This study provides a detailed cytoarchitectonic map of the prefrontal cortex enriched with receptor density and functional connectivity data.
- The authors shared the data via repositories and applied their map to a macaque MRI atlas to further facilitate data sharing.Weaknesses:
- The temporal cortex should be included in the functional connectivity analysis as it is known from anatomical studies that most prefrontal areas display rich connectivity with temporal areas. The aim of creating a comprehensive view of the frontal cortex makes the manuscript data-rich but cursory in discussing the relevant anatomical and functional literature. -
Reviewer #2 (Public Review):
Rapan and colleagues did perform an impressive multi-modal parcellation of the macaque frontal cortex. In addition to qualitative cytoarchitectonic and resting-state functional fMRI data analyses, the authors based their parcellation on quantitative receptor density analysis of 14 receptors. Compared with the classic Walker map of the macaque frontal cortex, the authors produced a more refined map. Those results should be discussed in light of previous work on the same topic (Petrides et al. 2012 Cortex; Reveley et al. 2017 Cerebral Cortex; Saleem and Logothetis 2012).
-
Reviewer #3 (Public Review):
The function of a brain area is defined by its interaction with other regions. Accordingly, two areas communicate via axons and dendrites, but the language is plurimodal along the neurotransmitter-receptor dimension. Consequently, reading its neurochemical constituents is the most advanced way to characterize the brain into functional territories.
Along this theoretical line of research, Rapan et al. produced an exceptional report on the structure of the macaque frontal lobes based on cytoarchitectural division complemented with functional connectivity and neurochemical data. Results are lavishly illustrated. They report 35 cytoarchitectural areas in the prefrontal lobe with precise, different connectivity and neurotransmitter profiles together with practical anatomical landmarks. All data is openly …
Reviewer #3 (Public Review):
The function of a brain area is defined by its interaction with other regions. Accordingly, two areas communicate via axons and dendrites, but the language is plurimodal along the neurotransmitter-receptor dimension. Consequently, reading its neurochemical constituents is the most advanced way to characterize the brain into functional territories.
Along this theoretical line of research, Rapan et al. produced an exceptional report on the structure of the macaque frontal lobes based on cytoarchitectural division complemented with functional connectivity and neurochemical data. Results are lavishly illustrated. They report 35 cytoarchitectural areas in the prefrontal lobe with precise, different connectivity and neurotransmitter profiles together with practical anatomical landmarks. All data is openly available to the community and will constitute a cornerstone for future neuroscientific research in the macaque frontal lobes.
I congratulate the authors for this already extraordinary work.
-
