Structure

The dorsolateral prefrontal cortex (DLPFC) is located on the convexity of the prefrontal cortex, superior to orbital frontal cortex and anterior to the premotor cortex. Architectonically, it is composed of granular neurons distinct from the pyramidal cells of the adjacent motor cortex. The DLPFC includes at least Brodmann areas 9 and 46, the areas that are homologous to those surrounding the principal sulcus in lower primates, which have been shown to be important in working memory (WM) function (see below). Some researchers include other frontal zones in the DLPFC, including parts of Brodmann areas 8 through 12, 45, 46, and 47, though 44, 45, and 47/12 have also been characterized as ventrolateral prefrontal cortex (Diamond 2002).

Dendrites in the DLPFC reach full maturity by the age of 12 months, plateauing in length until at least age 27 years (Diamond 2002). Glucose metabolism also reaches adult levels by 12 months. However, synaptic density continues to decrease, potentially into adolescence, or even adulthood, and the DLPFC is one of the last regions to myelinate, a process that may continue even into the second decade of life (Diamond 2002). The DLPFC has extensive cortico-cortico connections with other frontal lobe systems and with posterior association cortex. It is also part of a cortical-subcortical system involving the dorsomedial thalamic nucleus and basal ganglia (Cummings 1994). There are direct connections to the dorsolateral head of the caudate nucleus, the lateral aspect of the dorsomedial globus pallidus, and rostrolateral substantia nigra. There are also indirect connections through the dorsal globus pallidus and ventromedial subthalamic nucleus, with thalamic relays in the parvo- and magnocellular portions of the ventral anterior nucleus and the mediodorsal nucleus (Saint-Cyr et al. 2002).

Function

The connections noted above allow the DLPFC to function as the “executive” of the brain, controlling and modulating the functions of other areas. The DLPFC has been implicated in “higher-order” cognitive functioning and has been associated with performance on tasks assessing WM, fluency, planning, mental flexibility, initiation, switching, and abstraction. Corresponding neuropsychological tasks include Controlled Oral Word Association, Wisconsin Card Sort Test (WCST), list-learning recognition, Trail Making, and semantic fluency (Stuss et al. 2002).

Fluency

In addition to the inferior frontal cortex (Broca’s area), the DLPFC is activated in children and adults on verbal fluency tasks. There are connections between the DLPFC and superior temporal cortices, indicating that the DLPFC “modulates the responsivity of a neural system in the superior temporal gyrus,” mediating state changes in word generation (Friston et al. 1991). The left DLPFC has been most strongly associated with controlled or phonemic verbal fluency (Stuss et al. 1998). Lesions to the right DLPFC, in contrast, result in nonverbal or figural fluency deficits (Jones-Gottman and Milner 1977; Ruff et al. 1994).

Planning

Increased cerebral blood flow extending from premotor, supplementary motor, and anterior cingulate to the DLPFC is present on tasks with a planning component (e.g., Tower of London) (Dagher et al. 1999). More recent research has indicated that the use of repetitive transcranial magnetic stimulation (rTMS) over the DLPFC disrupts spatial planning skills (Basso et al. 2006).

Shifting

Activation of the DLPFC has been associated with rule shifting (Ravizza and Carter 2008). Researchers have indicated that there appears to be a dorsal circuit, including the DLPFC, which mediates response shifting (Shafritz et al. 2005). Shifting in attention appears to be modulated by the DLPFC in conjunction with the anterior cingulate (Kondo et al. 2004).

WM

The DLPFC has been implicated in several WM theories. Early theories, including the “labeled-line model,” posited by Goldman-Rakic, indicated that WM functioning is divided into “informationally constrained domains” (Goldman-Rakic and Leung 2002). Using ideas stemming from connectionist theories, each of these domains is a part of a wider network of sensory, motor, and limbic areas (Goldman-Rakic and Leung 2002). This theory uses evidence from the parietal and temporal visual streams that contends that the parietal lobe (dorsal stream) processes spatial information (where: the relation of objects across coordinates), while the temporal lobe (ventral stream) processes nonspatial (what: as in a visual image or object) information. Within this framework, the DLPFC processes spatial WM; the VLPFC processes object, or nonspatial, WM. Multiple animal and human studies have lent at least partial support to this model (Courtney et al. 1996), though other studies have provided contradictory evidence, primarily stating that spatial and object information are both processed across the lateral prefrontal cortex (D’Esposito et al. 1998; Rao et al. 1997).

Yet other theorists posit a different localized theory of a WM hierarchy, believing that the function of WM is based on the cytoarchitectonic areas of the brain (Petrides 1994). This theory, known as the two-stage model, posits that different cytoarchitectonic areas carry out different WM functions. Petrides (1994) has argued that the VLPFC (mainly the inferior frontal gyrus) is where information is received from posterior areas of the brain and consequently maintained (Petrides 1994). The mid-VLPFC is involved in disambiguating different aspects of retrieval; it selects between relevant and irrelevant information (Kostopoulos and Petrides 2003). The DLPFC is activated when the information needs to be monitored and/or manipulated.

The maintenance condition of Petrides’ theory may correspond with either the phonological loop or the visuospatial sketchpad in Baddeley’s model; the manipulation condition may be equated with the central executive system, presumed to be modality independent. Several animal and human studies have supported this model (McLaughlin et al. 2009; Petrides 1994, 2000).

Illness

Given the large area of cortex devoted to DLPFC and its widespread connections, it is not surprising that a variety of neurologic and psychiatric diseases commonly affect the DLPFC. Lesions of the dorsolateral cortex cause apathy and difficulty maintaining new goals. This can lead to significant self-neglect, referred to as “diogenes syndrome.” Individuals with this syndrome may function fairly well in an organized, structured environment, but will have difficulties navigating complex social situations (Malloy and Duffy 1994). Impairments on tasks associated with the DLPFC, as well as neuroimaging changes, have been shown in schizophrenia, attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, and mood disorders.

Neurological Disease

Frontotemporal dementia (FTD) results in focal, lobar degeneration of frontal and temporal structures, and hence executive functions subserved by DLPFC are often affected early in the course of FTD; apathy in FTD may be related to DLPFC dysfunction (Zamboni et al. 2008). Branches of the middle cerebral artery (MCA) perfuse DLPFC, and MCA stroke therefore commonly results in lesions to this area. Traumatic brain injury, particularly deceleration injuries, can also result in DLPFC lesions, although orbital frontal areas are more commonly injured. White matter diseases like multiple sclerosis and small vessel cerebrovascular disease often involve DLPFC through disruption of connections with subcortical and remote cortical structures.

Psychiatric Disease

Early research has indicated DLPFC abnormalities in schizophrenia (Weinberger et al. 1986). Individuals with schizophrenia show inefficient DLPFC functioning during performance on WM tasks, as assessed by fMRI (Manoach et al. 2000; Potkin et al. 2009). Symptoms of disorganization in schizophrenia have been related to DLPFC functioning (Goghari et al. 2010). DLPFC functioning, and its interaction with the cerebellum, has been shown to predict responsiveness to cognitive-behavioral therapy (Kumari et al. 2009).

Studies have shown that ADHD adults have structural abnormalities in the anterior cingulate and DLPFC (Seidman et al. 2006). Gansler et al. (1998) described differentiation between ADHD subtypes, with adults with ADHD with hyperactivity potentially having more deficits on tasks related to dorsolateral prefrontal cortex dysfunction. Yeo et al. (2003) noted that children with ADHD had a smaller right DLPFC region.

The pathophysiology of anxiety disorders involves frontal-subcortical connections, including the DLPFC. Given lack of dysfunction on the WCST, early research reported a lack of DLPFC dysfunction in obsessive-compulsive disorder (OCD) (Abbruzzese et al. 1995); however, though there are few completed studies, later research has indicated that this may not be the case. Individuals with OCD have greater activation in the DLPFC and other interconnected regions during the performance of a WM task (Nakao et al. 2009). Individuals with OCD have been demonstrated to have decreased gray matter volume in the left DLPFC (van den Heuvel et al. 2009).

Individuals with depression appear to have reduced activation in the DLPFC (Jaracz 2008). Recovery from depression appears to cause increases in DLPFC activity (Koenigs and Grafman 2009). Depressed bipolar individuals have shown decreased gray matter density in the right DLPFC (Brooks et al. 2009). In addition, they also appear to have attenuated right DLPFC activation on fMRI (Altshuler et al. 2008). Euthymic bipolar individuals have shown decreased right DLPFC activity in response to neutral, mild, and intense happy faces and decreased left DLPFC activity in response to neutral, mild, and intense fearful faces (Hassel et al. 2008). Similarly, Yurgelun-Todd et al. (2000) showed a reduction in DLPFC activation in response to fearful facial affect.

Cross-References