Subregions of DLPFC Display Graded yet Distinct Structural and Functional Connectivity

Abstract

The human dorsolateral prefrontal cortex (DLPFC; approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography (11 females and 13 males) and resting-state functional magnetic resonance imaging (fMRI; 57 females and 21 males) were employed to map out the patterns of connectivity from each DLPFC subregion. Structural connectivity demonstrated graded intraregional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that the dorsal-rostral subregions connections were restricted to other frontal and limbic areas, whereas the ventral-caudal region was widely connected to frontal, parietal, and limbic cortex. Functional connectivity analyses demonstrated that subregions of DLPFC were strongly interconnected to each other. The dorsal subregions were associated with the default mode network (DMN), while middle dorsal-rostral subregions were linked with the multiple demand network (MDN). The ventral-caudal subregion showed increased functional coupling with both DMN and MDN. Our results suggest that the connectivity of the DLPFC may be subdivided along a dorsorostral-ventrocaudal axis with differing (albeit graded) patterns of connectivity reflecting the integrative executive function of the DLPFC.SIGNIFICANCE STATEMENT Research has shown that the dorsolateral prefrontal cortex (DLPFC) plays a role in various executive functions. By dividing the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically, we explored their patterns of structural and functional connectivity. The patterns of connectivity within DLPFC subregions demonstrated graded intraregional connectivity. There were distinctive patterns of connectivity with other cortical areas in dorsal-rostral and ventral-caudal DLPFC subregions. Divisions across DLPFC subregions seem to align with their structural and functional connectivity. Our results suggest that DLPFC may be subdivided by the diagonal axis of the dorsal-ventral axis and rostral-caudal axis, supporting the framework of a functional organization along the anterior-posterior axis in the lateral PFC.

Keywords: dorsolateral prefrontal cortex; executive functions; functional connectivity; resting-state fMRI; structural connectivity; tractography.

Figure 1.

A, The location of the seven DLPFC areas used as seed regions for the connectivity analyses. Red arrow indicates the anterior-posterior axis of the lateral PFC. Black arrows represent each axis of the subregions of DLPFC. Brodmann area: BA; 9a: the anterior seed of BA9; 9p: the posterior seed of BA9; 9/46 da: the dorsal-anterior seed of BA9/46; 9/46 da: the dorsal-posterior seed of BA9/46; 46: BA46, 9/46va: the ventral-anterior seed of BA9/46; 9/46vp: the ventral-posterior seed of BA9/46. B, Intra-DLPFC structural connectivity. C, The structural connectivity between DLPFC seed regions and the limbic regions. D, The structural connectivity between DLPFC seed regions and the frontal and parietal regions. Each DLPFC seed is represented by a circle. Lines connecting ROIs are displayed if the probabilistic tractography exceed the minimum probability threshold in either 50% (thin line) or 75% (thick line) of the participants. FP = frontal pole; P.Op = Pars opercularis; P. Tri = Pars triangularis; P. Orb = Pars orbitalis; medOFC = medial orbitofrontal cortex; latOFC = lateral orbitofrontal cortex; SMA = supplementary motor area; M1 = primary motor cortex; S1 = primary somatosensory cortex; 7PC = BA 7 (SPC); IPS = inferior parietal sulcus; PFop, PFt, PF, PFcm, PFm = supramarginal gyrus; PGa = angular gyrus.

Figure 2.

Structural connectivity patterns of the DLPFC seed regions. Brodmann area: BA, 9a: the anterior seed of BA9, 9p: the posterior seed of BA9, 9/46 da: the dorsal-anterior seed of BA9/46, 9/46 da: the dorsal-posterior seed of BA9/46, 46: BA46, 9/46va: the ventral-anterior seed of BA9/46, 9/46vp: the ventral-posterior seed of BA9/46.

Figure 3.

Functional connectivity patterns of the DLPFC seed regions. Brodmann area: BA, 9a: the anterior seed of BA9, 9p: the posterior seed of BA9, 9/46 da: the dorsal-anterior seed of BA9/46, 9/46 da: the dorsal-posterior seed of BA9/46, 46: BA46, 9/46va: the ventral-anterior seed of BA9/46, 9/46vp: the ventral-posterior seed of BA9/46.

Figure 4.

Comparisons of the rsFC along the rostral-caudal axis. Circles indicate the DLPFC seed regions. Warm colors indicate the comparison from the rostral to the caudal regions. Cold colors indicate the comparison from the caudal to the rostral regions. Circles indicate the location of the DLPFC seed regions. Brodmann area: BA, 9a: the anterior seed of BA9, 9p: the posterior seed of BA9, 9/46 da: the dorsal-anterior seed of BA9/46, 9/46 da: the dorsal-posterior seed of BA9/46, 46: BA46, 9/46va: the ventral-anterior seed of BA9/46, 9/46vp: the ventral-posterior seed of BA9/46.

Figure 5.

Comparisons of the rsFC along the dorsal-ventral axis. Circles indicate the location of the DLPFC seed regions. Warm colors indicate the comparison from the rostral to the caudal regions. Cold colors indicate the comparison from the caudal to the rostral regions.

Figure 6.

A, The results of the structural (top) and functional (bottom) connectivity profiles of the DLPFC seed regions. The color scale for the structural connectivity results indicates connection probability, and the functional connectivity color scale indicates correlation coefficient. Negative correlations are not shown. B, Similarity analysis. An example of structural and functional connectivity matrix from seven DLPFC subregions. We computed the similarity for the patterns of connectivity of the DLPFC subregions. C, The results of the similarity analyses. ***p_{Bonferroni-corrected} < 0.05 (p < 0.00023). FP = frontal pole; BA = Brodmann's areas; medOFC = medial orbitofrontal cortex; latOFC= lateral orbitofrontal cortex; SMA= supplementary motor area; M1 = primary motor cortex; S1 = primary somatosensory cortex; 5 Ci, 5 M, 5L = BA 5 (SPC); 7PC, 7A, 7P, 7 M = BA 7 (SPC); IPS = inferior parietal sulcus; PFop, PFt, PF, PFcm, PFm = supramarginal gyrus; PGa, PGp = angular gyrus; STG = superior temporal gyrus; LAT = lateral temporal pole; MED = medial temporal pole; MTG = middle temporal gyrus; ITG = inferior temporal gyrus; FG = fusiform gyrus; PhG = parahippocampal gyrus; HG = Heschl's gyrus; LG1 = lingual gyrus next to fusiform gyrus; LG2 = medial lingual gyrus; ACC = anterior cingulate cortex; MCC = middle cingulate cortex; PCC = posterior cingulate cortex; INS = insula; CdN = caudate nucleus; PT = putamen; PL = pallidum; THA = thalamus; AMG = amygdala; HCP = hippocampus.