The dorsolateral prefrontal cortex (dlPFC or DLPFC) is an area in the prefrontal cortex of the primate brain. It is one of the most recently derived parts of the human brain. It undergoes a prolonged period of maturation which lasts into adulthood. The dlPFC is not an anatomical structure, but rather a functional one. It lies in the middle frontal gyrus of humans (i.e., lateral part of Brodmann's area (BA) 9 and 46Brodmann, 1909). In macaque monkeys, it is around the principal sulcus (i.e., in Brodmann's area 46Walker, 1940). Other sources consider that dlPFC is attributed anatomically to BA 9 and 46 and BA 8, 9 and 10.
The dlPFC has connections with the orbitofrontal cortex, as well as the thalamus, parts of the basal ganglia (specifically, the dorsal caudate nucleus), the hippocampus, and primary and secondary association areas of neocortex (including posterior temporal, parietal, and occipital areas). The dlPFC is also the end point for the dorsal pathway (stream), which is concerned with how to interact with stimuli.
An important function of the dlPFC is the executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, the dlPFC is not exclusively responsible for executive functions. All complex mental activity requires the additional cortical and subcortical circuits with which the dlPFC is connected. The dlPFC is also the highest cortical area that is involved in motor planning, organization and regulation.
Structure The dlPFC is composed of spatial selective neurons, which gives it a neural circuitry that encompasses the entire range of sub-functions necessary to carry out an integrated response, such as: sensory input, retention in short-term memory, and motor signaling. Historically, the dlPFC was defined by its connection to the superior temporal cortex, the posterior parietal cortex, the anterior and posterior cingulate, the premotor cortex, the retrosplenial cortex, and the neocerebellum. These connections allow the dlPFC to regulate the activity of those regions, as well as to receive information from and be regulated by those regions.
Anatomical and Functional Subdivisions Overview Research from the 2010s onward has revealed that the dlPFC is not a functionally homogeneous region, but comprises multiple distinct subregions with specialized connectivity patterns and cognitive functions. This functional heterogeneity helps explain the variability in dlPFC activation locations across neuroimaging studies.
Early Evidence for Functional Heterogeneity (2013) In 2013, meta-analytic connectivity modeling revealed a fundamental functional distinction within the right dlPFC, challenging the notion of a single, homogeneous region. Anterior-Ventral Cluster (MNI coordinates: 30, 43, 23) 'Network connectivity: Increased connectivity with anterior cingulate cortex (ACC) and left homotopic dlPFC
Functional profile: Attention and action inhibition Conflict resolution (Stroop task, Go/No-Go paradigms) Performance monitoring and error detection
Proposed role: Higher-order cognitive control and behavioral adjustment in situations requiring increased performance monitoring
Posterior-Dorsal Cluster (MNI coordinates: 37, 33, 32) Network connectivity: Increased connectivity with bilateral intraparietal sulcus (IPS) and left homotopic dlPFC.
Functional profile: Action execution Working memory (n-back, Sternberg tasks) Stimulus processing and motor planning
Proposed role: Executive operator for working memory manipulation and response implementation
The study demonstrated that these subdivisions showed consistent differences in both task-dependent and task-independent (resting-state) functional connectivity, suggesting fundamental differences in their neural organization.
Hierarchical Organization The 2013 findings supported a hierarchical organization along the anterior-posterior axis of the dlPFC:
Posterior regions: Involved in more basic processes of cognitive control, such as stimulus-response mapping and working memory maintenance. Anterior regions: Involved in more abstract processes such as performance monitoring and adjusting behavior when necessary.
This organization is consistent with the "cascade model" of prefrontal cortex organization, where progressively anterior regions support increasingly abstract representations and complex actions.
Multi-Modal Parcellation (2016) In 2016, a comprehensive multi-modal parcellation study using magnetic resonance imaging (MRI)-based measures of cortical architecture, function, connectivity, and topography further confirmed the complex organization of the dlPFC. The study identified multiple distinct areas within the dlPFC region, supporting earlier findings of functional heterogeneity. This work demonstrated that:
The dlPFC could be subdivided into anterior and posterior subdivisions based on connectivity patterns. These subdivisions showed distinct functional profiles in task-based fMRI studies. Microstructural properties varied systematically across dlPFC subregions.
Detailed Cytoarchitectonic Mapping (2022) A 2022 study provided high-resolution cytoarchitectonic mapping of the anterior dlPFC, identifying four distinct areas based on observer-independent analysis of cell-body distributions in post-mortem brains. Newly Identified Areas Superior Frontal Sulcus 1 (SFS1)
Location: Primarily within the depth of the superior frontal sulcus, extending to its banks. Cytoarchitecture: Prominent cell-dense layers II and IV; medium-sized pyramidal cells in layer III with slight size gradient; undivided layer V; sharp layer VI-white matter border. Structural connectivity: Dense fronto-parietal and fronto-limbic tracts; callosal fibers to contralateral dlPFC. Functional connectivity: Strong default mode network (DMN) affiliation, coupling with medial prefrontal cortex, precuneus, and angular gyrus. Task profile: Deactivated during working memory tasks (2-back > 0-back); activated during theory-of-mind and narrative processing. Functional role: Abstract reasoning, self-reflection, moral and social cognition. Volume: Approximately 754 ± 201 mm³.
Superior Frontal Sulcus 2 (SFS2)
Location: Ventral to SFS1, on the ascending ventral bank of the superior frontal sulcus, partly reaching the middle frontal gyrus surface. Cytoarchitecture: Thin layer II with no sharp border to layer III; very thin and blurry layer IV; gradient in pyramidal cell size across layer III (IIIa, IIIb, IIIc subdivisions); prominent layer VI. Structural connectivity: Links to superior parietal lobule, dorsal cingulate, and caudal superior frontal gyrus. Functional connectivity: Hybrid DMN ↔ Multiple-Demand Network (MDN) coupling; transitional node characteristics. Task profile: Mild activation in relational reasoning and social tasks; deactivation in high-load working memory. Functional role: Conceptual bridge mediating internal models with external rule structure. Volume: Approximately 578 ± 142 mm³.
Middle Frontal Gyrus 1 (MFG1)
Location: Occupies the surface of the anterior middle frontal gyrus; largest cortical thickness among anterior dlPFC areas. Cytoarchitecture: Large pyramidal cells in deeper layer III (subdivisions into IIIa, IIIb, IIIc); lower cell density in layer IIIa; visible but not highly prominent layer IV; well-developed infragranular layers V and VI (>50% of cortical width); diffuse white matter border. Structural connectivity: Massive bidirectional connectivity with parietal cortex (intraparietal sulcus, superior parietal lobule), premotor cortex, caudate nucleus, ACC; heavy superior longitudinal fasciculus (SLF) II/III terminations. Functional connectivity: Core MDN member; strongest and most stable MDN coupling across task states; anti-correlated with DMN. Task activation: Highest positive BOLD signal during working memory (2-back > 0-back), relational reasoning, gambling, and task-switching tasks; co-activates with parietal intraparietal sulcus. Functional role: Core executive operator implementing working memory manipulation, rule application, response inhibition; domain-general executive hub orchestrating goal maintenance and cognitive flexibility. Volume: Approximately 1,392 ± 278 mm³ (largest of the anterior areas).
Middle Frontal Gyrus 2 (MFG2)
Location: Ventral to MFG1, reaching into the ventrally neighboring frontomarginal sulcus or anterior middle frontal sulcus (when present). Cytoarchitecture: Relatively homogenous cell density and cell size across all layers due to absence of large pyramidal cells in layers III and V; dense layer II; broad, well-developed, cell-dense layer IV; densely packed layer VI; sharp white matter border. Structural connectivity: Moderate myelination; connections to inferior frontal sulcus, anterior insula, and mid-cingulate. Functional connectivity: Mixed MDN-salience network; gateway toward ventrolateral prefrontal cortex. Functional role: Integration of value and cognitive control; "executive-emotional broker". Volume: Approximately 1,069 ± 281 mm³.
Functional Integration Across Subregions The 2022 study demonstrated that cytoarchitectonic subdivisions map onto functional subdivisions:
Dorsal-Rostral Tier (SFS1, 9a, 9p)"Reflective Thinkers" Thinner, lightly myelinated cortex; Functions: Abstract reasoning, self-reflection, social cognition, theory of mind Network: Strong DMN membership Task profile: Activated during narrative and social tasks; deactivated during high-load working memory
Mid-Lateral Tier (MFG1, areas 9-46d and 46)"Integrators" Functions: Domain-general executive control, goal maintenance, cognitive flexibility Network: Core MDN membership Task profile: Robust activation across working memory, attention, inhibition, and relational reasoning tasks
Ventral-Caudal Tier (MFG2, areas a9-46v and p9-46v)"Executors" Thicker, heavily myelinated cortex; Functions: Concrete cognitive control, response selection, value integration, top-down modulation of motor programs Network: MDN with salience network contributions Task profile: Highest activation during working memory and decision-making with motor output
Microstructure-Function Relationship The study confirmed that microstructural properties mirror functional specialization:
Connectivity defines function: Dorsal dlPFC regions "listen" to the self-referential DMN; ventral regions "talk" to the executive MDN. Function defines behavior: These interactions yield the full repertoire of planning, working memory, reasoning, and self-monitoring. Structure supports both: Histological gradients show microstructural tuning along the same axes seen in functional gradients.
Network Integration The dlPFC subregions act as connector hubs between different large-scale brain networks:
Bridging subregions (e.g., 9-46d, a9-46v, SFS2) synchronize internal goal representations (DMN) with external task execution (MDN), dynamically reconfiguring as cognitive demands shift. Dorsal regions show greater coupling with self-referential processing networks and are involved in abstract, reflective cognition. Ventral regions show greater coupling with executive control and attention networks and are involved in concrete action control.
Sex Differences Cytoarchitectonic studies have revealed area-specific sex differences in anterior dlPFC regions:
Females show significantly larger volumes in areas SFS2 (right hemisphere, p < 0.022) and MFG1 (right hemisphere, p < 0.036) compared to males. Right SFS1 also shows larger volume in females (p < 0.047). These differences are observed despite males having larger total brain volumes. No significant differences were found in the volume fraction of cell bodies (cytoarchitecture) between sexes These volumetric differences may relate to documented behavioral variations in cognitive control strategies, though functional implications require further investigation.
Clinical Relevance