Introduction

Why are we capable of doing things that are difficult, of making choices to go the hard route or the extra mile? Much of this ability can be attributed to the bulk of the frontal cortex in an area known as the prefrontal cortex (PFC). One of the last places in the brain to mature, the prefrontal cortex is thought of as the “personality center” and is the cortical region that makes us uniquely human. It is where we process moment-to-moment input from our surroundings, compare that input to past experiences, and then react to them. It is where we manifest our insight, foresight, and planning capabilities into the actions that define who we are. Lesions in this area produce a number of neuropsychiatric disorders that tend to present with disinhibition, apathy, loss of initiative, and personality changes. Discoveries are still being made about the role the PFC plays within our lives and how various dysfunctions alter its function.[1][2][3][4]

Structure and Function

Our understanding of the role of the PFC was serendipitously advanced in 1848 when Phineas Gage had a rare accident in which an iron tamping rod pierced through what now is known as the orbitofrontal lobe. Phineas, a once respectable loving husband and father, became short-tempered, brash, and prone to devise and then immediately abandon any plans he made.

The PFC is unique because it is not a purely sensory nor purely motor component of the brain. Instead, the PFC receives input from multiple cortical regions to process "in the moment" information. Through connections to other cortical areas, the PFC processes higher-order executive functions. These reciprocal connections make it possible to adapt to different situational surroundings and control reactions based on a person's perception at a particular moment. Its ability to properly integrate incoming information is crucial for survival during interactions in the social world, and as such, pro-social skills are more highly developed in humans versus other primate and non-primate animals.[5][6]

Through observing humans and other primates with specific PFC lesions, certain locations are associated with particular deficits. In this roundabout way we have begun to understand some of its functions; for example, the dorsolateral PFC tends to be associated with planning, strategy, and executive decisions while the orbitofrontal region is related to inhibiting primal survival responses arising from the primitive limbic system. The PFC also is believed to play a role in our emotional state through its extensive connections to areas controlling the release of the mood-altering neurotransmitters dopamine, norepinephrine, and serotonin. Therefore, PFC dysfunction has been implicated in neuropsychiatric disorders as imaging reveals decreased PFC activity in depressed patients and those with schizophrenia.

Embryology

Along with the remainder of the nervous system, the embryologic beginnings of the PFC start at week three within the neural plate. With continued development, the neural plate forms the neural groove which then seals off from the amniotic fluid to form the neural tube. In the fourth week of gestation, the prosencephalon bulges laterally out of the rostral neural tube; this further differentiates into the telencephalon which becomes the cerebral cortex. Like the rest of the central nervous system, the PFC has an initial overgrowth of neurons and their synaptic connections, and extensive pruning of the excess occurs in utero and during early childhood to create adult-like delineated pathways.

Blood Supply and Lymphatics

The PFC is supplied by the internal carotid artery which gives rise to the anterior and middle cerebral arteries. The lateral and anterior aspects of the PFC is mainly supplied via the middle cerebral artery, whereas the superior and medial surfaces are supplied by the anterior cerebral artery. The middle cerebral artery provides the prerolandic and orbitofrontal branches, and the anterior cerebral artery provides the orbital, frontopolar, and callosomarginal branches. Venous drainage of the PFC is via superficial cerebral veins which drain into the superior and inferior sagittal sinuses.

The brain was not thought to have true lymphatics; however, recent evidence shows the presence of lymphatic drainage referred to as the “glymphatic system” or “glial-related lymphatics.” This glymphatic interstitial fluid collects within perivenous spaces. It then follows the meningeal sinuses, large deep veins, and lateral-ventral caudal rhinal veins to drain primarily into cervical lymph nodes. 

Nerves

No discreet peripheral nerves directly stimulate the prefrontal cortex. Instead, the PFC receives and sends connections to many cortical, subcortical, and brainstem regions via fasciculi (bundles of axons which serve a similar function). Large association bundles, e.g., the superior and inferior occipitofrontal fasciculi, as well as the cingulum and uncinate fasciculi, form reciprocal connections between the PFC and primary sensory and motor cortices and their association areas.

Physiologic Variants

Physiologic variants have been found in individuals with neuropsychiatric disorders and those exposed to early childhood stressors. In depressed patients, decreased activity within the PFC has been revealed by near-infrared spectroscopy and messenger RNA assays which showed down-regulation of glutamate transporter genes. Functional MRI studies have shown patients with schizophrenia have reduced long-interval cortical inhibition and hypoactivity. The PFC also can be severely malformed or reduced in volume as a result of the developmental disorder holoprosencephaly.

Surgical Considerations

Motor mapping in sedated patients or sensorimotor and language mapping in awake anesthetized patients is utilized in frontal lobe neurosurgery. These techniques help surgeons to determine the discreet anatomy of a patient’s brain in an attempt to decrease the amount of surgical intrusion into areas which may cause dramatic neurologic deficits. However, it should be noted that these motor and language areas lie posterior to the PFC proper.[7][8][9][5]

Clinical Significance

The PFC can be divided into two broad regions, each with a different function: the lateral PFC (dorsolateral prefrontal cortex and ventrolateral prefrontal cortex) and the ventromedial PFC (also known as the orbitofrontal PFC). Lesions in the dorsolateral PFC tend to cause a loss of working memory and/or an inability to perform delayed response tasks. Furthermore, there are impairments in memory recall and the context in which the memory was originally founded. This causes patients to have difficulty switching tasks and dealing with changes in rules during testing. In contrast to the dorsolateral PFC, lesions in the ventromedial PFC result in confabulation. Ventromedial PFC lesions also can present with poor judgment, emotional lability, inappropriate affect, and distractibility.

As previously stated, dysfunction and dysregulation of neurotransmitters and their respective receptors within the PFC are found in patients with neuropsychiatric disorders. Patients with depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and attention deficit hyperactivity disorders have been studied.