What Do We Know About the Prefrontal Cortex?

We hear a lot these days about the prefrontal

cortex. Dysfunction of this brain region are important in attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease. Eager to find a physical location for what makes us human, we search there for the ego, the conscious mind, the self, and even the soul.

When I was in medical school, the frontal lobe of the brain, along with vast areas of the parietal and temporal lobes, was a dark continent. We knew the primary motor strip stretched along the rear edge of the frontal lobe, and we could locate its neighbor, the somatosensory cortex, represented by a grinning homunculus, across the central sulcus on front of the parietal lobe. The occipital lobe contained the visual cortex, the auditory cortex occupied a small region of the parietal lobe, and Wernicke’s and Broca’s areas in the temporal and parietal cortexes were the centers for receptive and expressive language. Microscopists had much earlier traced projections from lower areas of the brain to various cortical areas, as well as extensive connections among cortical areas themselves. Case studies of patients with brain injuries and postmortem studies had associated cognitive deficits with certain areas, but there was no pattern that made much sense.

In the last few decades, functional neuroimaging, which measures metabolic or electrical activity in particular regions of living brains, as well as animal studies using electrodes to capture the activity of single neurons or to stimulate small areas, have begun to delineate how the cortex functions. These techniques can be combined with psychological tests. While the picture is far from complete, it is doubtful that any function is truly localized to the prefrontal cortex. Damage to the prefrontal cortex results in impaired executive functioning, for example, but dynamic connections with lower areas of the brain, other cortical areas, and between and within specific parts of the prefrontal cortex itself are also necessary for executive functioning.

The prefrontal cortex is huge. It stretches like the cowling from the horizontal area above the eye sockets over the front and sides of each hemisphere of the brain. Most discussions divide it into regions based on location: orbital, ventrolateral, ventromedial, dorsolateral, and dorsomedial; some findings are lateralized to the left or right hemisphere. At the cellular level, its pyramidal cells have more and more complex connections that similar cells in posterior regions such as the visual cortex in the occipital lobe.

The prefrontal cortex connects reciprocally to many other areas of the brain, especially motor and sensory areas. A mostly unidirectional path carries output from to the circuits of the basal ganglia, which send their output to the thalamus, which in turn projects back to the prefrontal cortex. The orbital prefrontal cortex also has close connections with limbic structures critical for long-term memory, affect, and motivation. These include the amygdala, nucleus accumbens, and hypothalamus. The prefrontal cortex does not simply receive and process information—it is the most complex part of a dynamic system involving many other components.

Electrical stimulation of the prefrontal cortex has no obvious effect, and damage from brain injury (the most famous case is Phineas Gage), tumor, or stroke,may not affect language, memory, or other functions measured on standard intelligence tests. Such individuals are capable of conditioned learning. But they may be show impulsivity, inability to consider longer-term goals, disinhibition, irritability, and difficulty recognizing the emotions of other people. They have trouble planning and making decisions.

Functional neuroimaging of humans and lesion studies in monkeys are beginning to localize functions within the prefrontal cortex. Orbital and medial areas activate during tasks involving reward, motivation, and emotional decision-making. Ventrolateral areas are involved with holding information in working memory, while dorsolateral areas are active during manipulation of information. The most anterior area—the frontal pole—may be involved in transferring information between dorsolateral and ventrolateral areas.

Neurons in the prefrontal cortex are capable of sustained activity, which may function to keep information “on line,” in working memory. The signal to sustain activity may come from dopaminergic neurons in the midbrain. Different neurons in the prefrontal cortex are active during different tasks involving the application of different rules, such as matching by location versus association. But at least some neurons demonstrate flexibility: they can handle more than one rule and switch back and forth rapidly.

Although no one has yet proposed a model to explain the overall functioning of the prefrontal cortex and its connections, several theoretical approaches have been proposed. The neurologist Antonio Damasio’s Somatic Marker Hypotheses proposes that memories of affectively-laden events are associated with “somatic markers,” which are physiological affect states. A somatic marker functions to rapidly apply past experience in evaluating current situations. Another set of theories proposes processing levels within the prefrontal cortex: first, the ventrolateral areas receive input from sensory cortical areas, then dorsolateral areas process the information by monitoring behaviors and manipulating information. Another line of work suggests that abstraction increases with more frontal areas: associations of stimuli with simple motor responses are handled by the premotor cortex, which is right behind the prefrontal cortex, more abstract rules activate lateral prefrontal areas, and context-dependent rules involve the most anterior areas.

The dynamic flexibility of the prefrontal cortex may explain the limitations of executive function. Sustained activation is necessary for working memory, which is thought to have a central role in cognitive control. This is the active, short-term memory necessary for complex, goal-directed behaviors that extend over time. Long-term memory requires changing the strength of synapses, which depends on slower processes such as protein synthesis. It has much greater capacity than sustained activation, but is also much slower, since the information is accessible only when the synapses are activated. The sustained activation of distributed networks involved in cognitive control has much more limited capacity. An analogy is the difference between a computer’s RAM, the active memory, and its hard drive, although as a biological system, the brain’s connections and processes are far more flexible and dynamic than a computer’s.

Evidence suggests that rapid, on-off processing of information takes place in the basal ganglia; this is the basis of habit-based responses. In contrast, the prefrontal cortex operates more slowly but is able to maintain the entire model of a complex task from beginning to end.

These are some aspects of the emerging picture of the prefrontal cortex’s dynamic functioning. Like everything else about the brain, it is breathtaking clear how much more we have to learn. While the prefrontal cortex is central to our complex human brains, it does not act alone. It is necessary for executive functioning and other higher cognitive, emotional, and social functions, but it produces these only in dynamic interaction with other parts of the brain, especially the basal ganglia, the reward system, and sensory cortices, and via the sensory cortices, with other people and the environment. Much of what we consider human depends on the prefrontal cortex, and most psychiatric illness is likely to involve dysfunctions in prefrontal regions as well as other brain areas.

Further reading: Earl K. Miller and Jonathan D. Wallis, The Prefrontal Cortex and Executive Brain Functions. In Fundamental Neuroscience, Fourth Edition, Larry Squire et al., Editors, 2012. pp. 1069-1090.

Picture: Phineas Gage and the tamping rod that injured his brain.

Recent Posts