The dorsolateral prefrontal cortex (DLPFC or DL-PFC) is an area in the prefrontal cortex
of the brain of humans and other primates. It is one of the most
recently derived parts of the human brain. It undergoes a prolonged
period of maturation which lasts until 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 46). In macaque monkeys, it is around the principal sulcus (i.e., in Brodmann's area 46). 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 the 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
As the DLPFC is composed of spatial selective neurons,
it has 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.
Function
Primary functions
The DLPFC is known for its involvement in the executive functions, which is an umbrella term for the management of cognitive processes, including working memory, cognitive flexibility, and planning. A couple of tasks have been very prominent in the research on the DLPFC, such as the A-not-B task, the delayed response task and object retrieval tasks.
The behavioral task that is most strongly linked to DLPFC is the
combined A-not-B/delayed response task, in which the subject has to find
a hidden object after a certain delay. This task requires holding
information in mind (working memory), which is believed to be one of the functions of DLPFC.
The importance of DLPFC for working memory was strengthened by studies
with adult macaques. Lesions that destroyed DLPFC disrupted the
macaques’ performance of the A-not-B/delayed response task, whereas
lesions to other brain parts did not impair their performance on this
task.
DLPFC is not required for the memory of a single item. Thus, damage to the dorsolateral prefrontal cortex does not impair recognition memory.
Nevertheless, if two items must be compared from memory, the
involvement of DLPFC is required. People with damaged DLPFC are not able
to identify a picture they had seen, after some time, when given the
opportunity to choose from two pictures. Moreover, these subjects also failed in Wisconsin Card-Sorting Test as they lose track of the currently correct rule and persistently organize their cards in the previously correct rule. In addition, as DLPFC deals with waking thought and reality testing, it is not active when one is asleep. Likewise, DLPFC is most frequently related to the dysfunction of drive, attention and motivation.
Patients with minor DLPFC damage display disinterest in their
surroundings and are deprived of spontaneity in language as well as
behavior. Patients may also be less alert than normal to people and events they know. Damage to this region in a person also leads to the lack of motivation to do things for themselves and/or for others.
Decision making
The DLPFC is involved in both risky and moral decision making; when individuals have to make moral decisions like how to distribute limited resources, the DLPFC is activated. This region is also active when costs and benefits of alternative choices are of interest.
Similarly, when options for choosing alternatives are present, the
DLPFC evokes a preference towards the most equitable option and
suppresses the temptation to maximize personal gain.
Working memory
Working
memory is the system that actively holds multiple pieces of transitory
information in the mind, where they can be manipulated. The DLPFC is
important for working memory; reduced activity in this area correlates to poor performance on working memory tasks. However, other areas of the brain are involved in working memory as well.
There is an ongoing discussion if the DLPFC is specialized in a certain type of working memory, namely computational mechanisms for monitoring and manipulating items, or if it has a certain content, namely visuospatial information, which makes it possible to mentally represent coordinates within the spatial domain.
There have also been some suggestions that the function of the
DLPFC in verbal and spatial working memory is lateralised into the left
and right hemisphere, respectively. Smith, Jonides and Koeppe (1996)
observed a lateralisation of DLPFC activations during verbal and visual
working memory. Verbal working memory tasks mainly activated the left
DLPFC and visual working memory tasks mainly activated the right DLPFC.
Murphy et al. (1998)
also found that verbal working memory tasks activated the right and
left DLPFC, whereas spatial working memory tasks predominantly activated
the left DLPFC. Reuter-Lorenz et al. (2000)
found that activations of the DLPFC showed prominent lateralisation of
verbal and spatial working memory in young adults, whereas in older
adults this lateralisation was less noticeable. It was proposed that
this reduction in lateralisation could be due to recruitment of neurons
from the opposite hemisphere to compensate for neuronal decline with
ageing.
Secondary functions
The DLPFC may also be involved in the act of deception and lying, which is thought to inhibit normal tendency to truth telling. Research also suggests that using TMS on the DLPFC can impede a person's ability to lie or to tell the truth.
Additionally, supporting evidence suggests that the DLPFC may
also play a role in conflict-induced behavioral adjustment, for instance
when an individual decides what to do when faced with conflicting
rules. One way in which this has been tested is through the Stroop test,
in which subjects are shown a name of a color printed in colored ink
and then are asked to name the color of the ink as fast as possible.
Conflict arises when the color of the ink does not match the name of the
printed color. During this experiment, tracking of the subjects’ brain
activity showed a noticeable activity within the DLPFC.
The activation of the DLPFC correlated with the behavioral performance,
which suggests that this region maintains the high demands of the task
to resolve conflict, and thus in theory plays a role in taking control.
DLPFC may also be associated with human intelligence. However,
even when correlations are found between the DLPFC and human
intelligence, that does not mean that all human intelligence is a
function of the DLPFC. In other words, this region may be attributed to
general intelligence on a broader scale as well as very specific roles,
but not all roles. For example, using imaging studies like PET and fMRI indicate DLPFC involvement in deductive, syllogistic reasoning. Specifically, when involved in activities that require syllogistic reasoning, left DLPFC areas are especially and consistently active.
The DLPFC may also be involved in threat-induced anxiety.
In one experiment, participants were asked to rate themselves as
behaviorally inhibited or not. Those who rated themselves as
behaviorally inhibited, moreover, showed greater tonic (resting)
activity in the right-posterior DLPFC. Such activity is able to be seen through Electroencephalogram
(EEG) recordings. Individuals who are behaviorally inhibited are more
likely to experience feelings of stress and anxiety when faced with a
particularly threatening situation. In one theory, anxiety susceptibility may increase as a result of present vigilance. Evidence for this theory includes neuroimaging studies that demonstrate DLPFC activity when an individual experiences vigilance.
More specifically, it is theorized that threat-induced anxiety may also
be connected to deficits in resolving problems, which leads to
uncertainty.
When an individual experiences uncertainty, there is increased activity
in the DLPFC. In other words, such activity can be traced back to
threat-induced anxiety.
Social cognition
Among
the prefrontal lobes, the DLPFC seems to be the one that has the least
direct influence on social behavior, yet it does seem to give clarity
and organization to social cognition.
The DLPFC seems to contribute to social functions through the operation
of its main speciality the executive functions, for instance when
handling complex social situations. Social areas in which the role of the DLPFC is investigated are, amongst others, social perspective taking and inferring the intentions of other people, or theory of mind; the suppression of selfish behavior, and commitment in a relationship.
Relation to neurotransmitters
As
the DLPFC undergoes long maturational changes, one change that has been
attributed to the DLPFC for making early cognitive advances is the
increasing level of the neurotransmitter dopamine in the DLPFC.
In studies where adult macaques' dopamine receptors were blocked, it
was seen that the adult macaques had deficits in the A-not-B task, as if
the DFPLC was taken out altogether. A similar situation was seen when
the macaques were injected with MPTP, which reduces the level of dopamine in the DLPFC. Even though there have been no physiological studies about involvement of cholinergic actions in sub-cortical areas, behavioral studies indicate that the neurotransmitter acetylcholine is essential for working memory function of the DLPFC.
Clinical significance
Schizophrenia
Schizophrenia may be partially attributed to a lack in activity in the frontal lobe. The dorsolateral prefrontal cortex is especially underactive when a person suffers from chronic schizophrenia. Schizophrenia is also related to lack of dopamine neurotransmitter in the frontal lobe. The DLPFC dysfunctions are unique among the schizophrenia patients as
those that are diagnosed with depression do not tend to have the same
abnormal activation in the DLPFC during working memory-related tasks.
Working memory is dependent upon the DLPFC’s stability and
functionality, thus reduced activation of the DLPFC causes schizophrenic
patients to perform poorly on tasks involving working memory. The poor
performance contributes to the added capacity limitations in working
memory that is greater than the limits on normal patients.
The cognitive processes that deal heavily with the DLPFC, such as
memory, attention, and higher order processing, are the functions that
once distorted contribute to the illness.
Depression
Along with regions of the brains such as the limbic system, the dorsolateral prefrontal cortex deals heavily with major depressive disorder
(MDD). The DLPFC may contribute to depression due to being involved
with the disorder on an emotional level during the suppression stage. While working memory tasks seem to activate the DLPFC normally, its decreased grey matter volume correlates to its decreased activity. The DLPFC may also have ties to the ventromedial prefrontal cortex in their functions with depression.
This can be attributed to how the DLPFC’s cognitive functions can also
involve emotions, and the VMPFC’s emotional effects can also involve
self-awareness or self-reflection. Damage or lesion to the DLPFC can
also lead to increased expression of depression symptoms.
Stress
Exposure to severe stress may also be linked to damage in the DLPFC. More specifically, acute stress has a negative impact on the higher cognitive function known as working memory (WM), which is also traced to be a function of the DLPFC. In an experiment, researchers used functional magnetic resonance imaging (fMRI) to record the neural activity in healthy individuals who participated in tasks while in a stressful environment.
When stress successfully impacted the subjects, their neural activity
showed reduced working memory related activity in the DLPFC.
These findings not only demonstrate the importance of the DLPFC region
in relation to stress, but they also suggest that the DLPFC may play a
role in other psychiatric disorders. In patients with post-traumatic stress disorder (PTSD), for example, daily sessions of right dorsolateral prefrontal repetitive transcranial magnetic stimulation (rTMS) at a frequency of 10 Hz resulted in more effective therapeutic stimulation.
Substance abuse
Substance abuse of drugs, or substance use disorder (SUD), may correlate with dorsolateral prefrontal cortex dysfunction.
Those who abuse drugs have been shown to engage in increased risky
behavior, possibly correlating with a dysfunction of the DLPFC. The
executive controlling functions of the DLPFC in individuals who display
drug abuse may have a connection that is lessen from risk factoring
areas such as the anterior cingulate cortex and insula.
This weakened connection is even shown in healthy subjects, such as a
patient who continued to make risky decisions with a disconnect between
their DLPFC and insula. Lesions of the DLPFC may result in
irresponsibility and freedom from inhibitions, and the abuse of drugs can invoke the same response of willingness or inspiration to engage in daring activity.
Alcohol
Alcohol creates deficits on the function of the prefrontal cortex.
As the anterior cingulate cortex works to inhibit any inappropriate
behaviors through processing information to the executive network of the
DLPFC,
as noted before this disruption in communication can lead to these
actions being made. In a task known as Cambridge risk task, SUD
participants have been shown to have a lower activation of their DLPFC.
Specifically in a test related to alcoholism, a task called the Wheel of
Fortune (WOF) had adolescents with a family history of alcoholism
present lower DLPFC activation. Adolescents that have had no family members with a history of alcoholism did not exhibit the same decrease of activity.
Tissue
slice from the brain of an adult macaque monkey (Macaca mulatta). The
cerebral cortex is the outer layer depicted in dark violet. Source:
BrainMaps.org
In most mammals, apart from small mammals that have small brains,
the cerebral cortex is folded, providing a greater surface area in the
confined volume of the cranium. Apart from minimising brain and cranial volume, cortical folding is crucial for the wiring of the brain and its functional organisation. In mammals with a small brain there is no folding and the cortex is smooth.
A fold or ridge in the cortex is termed a gyrus (plural gyri) and a groove is termed a sulcus (plural sulci). These surface convolutions appear during fetal development and continue to mature after birth through the process of gyrification. In the human brain the majority of the cerebral cortex is not visible from the outside, but buried in the sulci, and the insular cortex is completely hidden. The major sulci and gyri mark the divisions of the cerebrum into the lobes of the brain.
There are between 14 and 16 billion neurons in the human cerebral cortex. These are organised into horizontal layers, and radially into cortical columns and minicolumns. Cortical areas have specific functions such as movement in the motor cortex, and sight in the visual cortex.
Structure
Lateral view of cerebrum showing several cortices
The cerebral cortex is the outer covering of the surfaces of the cerebral hemispheres and is folded into peaks called gyri, and grooves called sulci. In the human brain it is between two and three or four millimetres thick, and makes up 40 per cent of the brain's mass. 90 per cent of the cerebral cortex is the six-layered neocortex with the other 10 per cent made up of allocortex. There are between 14 and 16 billion neurons in the cortex, and these are organized radially in cortical columns, and minicolumns, in the horizontally organized layers of the cortex.
The neocortex is separable into different regions of cortex known in the plural as cortices, and include the motor cortex and visual cortex. About two thirds of the cortical surface is buried in the sulci and the insular cortex is completely hidden. The cortex is thickest over the top of a gyrus and thinnest at the bottom of a sulcus.
Folds
The cerebral cortex is folded in a way that allows a large surface area of neural tissue to fit within the confines of the neurocranium. When unfolded in the human, each hemispheric cortex has a total surface area of about 0.12 square metres (1.3 sq ft).
The folding is inward away from the surface of the brain, and is also
present on the medial surface of each hemisphere within the longitudinal fissure.
Most mammals have a cerebral cortex that is convoluted with the peaks
known as gyri and the troughs or grooves known as sulci. Some small
mammals including some small rodents have smooth cerebral surfaces without gyrification.
For species of mammals, larger brains (in absolute terms, not just in relation to body size) tend to have thicker cortices. The smallest mammals, such as shrews,
have a neocortical thickness of about 0.5 mm; the ones with the largest
brains, such as humans and fin whales, have thicknesses of 2–4 mm. There is an approximately logarithmic relationship between brain weight and cortical thickness.
Magnetic resonance imaging of the brain
(MRI) makes it possible to get a measure for the thickness of the human
cerebral cortex and relate it to other measures. The thickness of
different cortical areas varies but in general, sensory cortex is
thinner than motor cortex. One study has found some positive association between the cortical thickness and intelligence.
Another study has found that the somatosensory cortex is thicker in migraine sufferers, though it is not known if this is the result of migraine attacks or the cause of them.
A later study using a larger patient population reports no change in the cortical thickness in migraine sufferers.
A genetic disorder of the cerebral cortex, whereby decreased folding in certain areas results in a microgyrus, where there are four layers instead of six, is in some instances seen to be related to dyslexia.
Layers of neocortex
Diagram of layers pattern. Cells grouped on left, axonal layers on right.
Three drawings of cortical lamination by Santiago Ramon y Cajal, each showing a vertical cross-section, with the surface of the cortex at the top. Left: Nissl-stained visual cortex of a human adult. Middle: Nissl-stained motor cortex of a human adult. Right: Golgi-stained cortex of a 11⁄2 month old infant. The Nissl stain shows the cell bodies of neurons; the Golgi stain shows the dendrites and axons of a random subset of neurons.
The neocortex is formed of six layers, numbered I to VI, from the outermost layer I – near to the pia mater, to the innermost layer VI – near to the underlying white matter.
Each cortical layer has a characteristic distribution of different
neurons and their connections with other cortical and subcortical
regions. There are direct connections between different cortical areas
and indirect connections via the thalamus.
Staining
cross-sections of the cortex to reveal the position of neuronal cell
bodies and the intracortical axon tracts allowed neuroanatomists in the
early 20th century to produce a detailed description of the laminar structure of the cortex in different species. The work of Korbinian Brodmann (1909) established that the mammalian neocortex is consistently divided into six layers.
Layer I
Layer I is the molecular layer, and contains few scattered neurons, including GABAergicrosehip neurons. Layer I consists largely of extensions of apical dendritic tufts of pyramidal neurons and horizontally oriented axons, as well as glial cells. During development, Cajal-Retzius cells and subpial granular layer cells are present in this layer. Also, some spiny stellate cells can be found here. Inputs to the apical tufts are thought to be crucial for the feedback interactions in the cerebral cortex involved in associative learning and attention. While it was once thought that the input to layer I came from the cortex itself, it is now realized that layer I across the cerebral cortex mantle receives substantial input from matrix or M-type thalamus cells (in contrast to core or C-type that go to layer IV).
Layer III, the external pyramidal layer,
contains predominantly small and medium-size pyramidal neurons, as well
as non-pyramidal neurons with vertically oriented intracortical axons;
layers I through III are the main target of interhemispheric
corticocortical afferents, and layer III is the principal source of corticocortical efferents.
Layer IV
Layer IV, the internal granular layer, contains different types of stellate and pyramidal cells, and is the main target of thalamocortical afferents from thalamus type C neurons (core-type )
as well as intra-hemispheric corticocortical afferents. The layers
above layer IV are also referred to as supragranular layers (layers
I-III), whereas the layers below are referred to as infragranular layers
(layers V and VI).
Layer V
Layer V, the internal pyramidal layer, contains large pyramidal neurons. Axons from these leave the cortex and connect with subcortical structures including the basal ganglia. In the primary motor cortex of the frontal lobe, layer V contains giant pyramidal cells called Betz cells, whose axons travel through the internal capsule, the brain stem, and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control.
Layer VI
Layer
VI, the polymorphic or multiform layer, contains few large pyramidal
neurons and many small spindle-like pyramidal and multiform neurons;
layer VI sends efferent fibers to the thalamus, establishing a very
precise reciprocal interconnection between the cortex and the thalamus.
That is, layer VI neurons from one cortical column connect with
thalamus neurons that provide input to the same cortical column. These
connections are both excitatory and inhibitory. Neurons send excitatory fibers to neurons in the thalamus and also send collaterals to the thalamic reticular nucleus that inhibit these same thalamus neurons or ones adjacent to them. One theory is that because the inhibitory output is reduced by cholinergic input to the cerebral cortex, this provides the brainstem with adjustable "gain control for the relay of lemniscal inputs".
Columns
The
cortical layers are not simply stacked one over the other; there exist
characteristic connections between different layers and neuronal types,
which span all the thickness of the cortex. These cortical microcircuits
are grouped into cortical columns and minicolumns. It has been proposed that the minicolumns are the basic functional units of the cortex. In 1957, Vernon Mountcastle
showed that the functional properties of the cortex change abruptly
between laterally adjacent points; however, they are continuous in the
direction perpendicular to the surface. Later works have provided
evidence of the presence of functionally distinct cortical columns in
the visual cortex (Hubel and Wiesel, 1959), auditory cortex,
and associative cortex.
Cortical areas that lack a layer IV are called agranular. Cortical areas that have only a rudimentary layer IV are called dysgranular.
Information processing within each layer is determined by different
temporal dynamics with that in layers II/III having a slow 2 Hzoscillation while that in layer V has a fast 10–15 Hz oscillation.
Types of cortex
Based on the differences in laminar organization the cerebral cortex can be classified into two types, the large area of neocortex which has six cell layers, and the much smaller area of allocortex that has three or four layers:
The neocortex is also known as the isocortex or neopallium and
is the part of the mature cerebral cortex with six distinct layers.
Examples of neocortical areas include the granular primary motor cortex, and the striate primary visual cortex. The neocortex has two subtypes, the true isocortex and the proisocortex which is a transitional region between the isocortex and the regions of the periallocortex.
The allocortex is the part of the cerebral cortex with three or four layers, and has three subtypes, the paleocortex with three cortical laminae, the archicortex which has four or five, and a transitional area adjacent to the allocortex, the periallocortex. Examples of allocortex are the olfactory cortex and the hippocampus.
There is a transitional area between the neocortex and the allocortex called the paralimbic cortex,
where layers 2, 3 and 4 are merged. This area incorporates the
proisocortex of the neocortex and the periallocortex of the allocortex.
In addition, the cerebral cortex may be classified into four lobes: the frontal lobe, temporal lobe, the parietal lobe, and the occipital lobe, named from their overlying bones of the skull.
Blood supply and drainage
Arterial supply showing the regions supplied by the posterior, middle, and anterior cerebral arteries.
Blood supply to the cerebral cortex is part of the cerebral circulation. Cerebral arteries supply the blood that perfuses the cerebrum. This arterial blood carries oxygen, glucose, and other nutrients to the cortex. Cerebral veins drain the deoxygenated blood, and metabolic wastes including carbon dioxide, back to the heart.
The main arteries supplying the cortex are the anterior cerebral artery, the middle cerebral artery, and the posterior cerebral artery.
The anterior cerebral artery supplies the anterior portions of the
brain, including most of the frontal lobe. The middle cerebral artery
supplies the parietal lobes, temporal lobes, and parts of the occipital
lobes. The middle cerebral artery splits into two branches to supply the
left and right hemisphere, where they branch further. The posterior
cerebral artery supplies the occipital lobes.
The circle of Willis is the main blood system that deals with blood supply in the cerebrum and cerebral cortex.
Cortical blood supply
Development
The prenatal development of the cerebral cortex is a complex and finely tuned process called corticogenesis, influenced by the interplay between genes and the environment.
Neural tube
The cerebral cortex develops from the most anterior part, the forebrain region, of the neural tube. The neural plate folds and closes to form the neural tube. From the cavity inside the neural tube develops the ventricular system, and, from the neuroepithelial cells of its walls, the neurons and glia of the nervous system. The most anterior (front, or cranial) part of the neural plate, the prosencephalon, which is evident before neurulation begins, gives rise to the cerebral hemispheres and later cortex.
Neurogenesis is shown in red and lamination is shown in blue. Adapted from (Sur et al. 2001)
The cerebral cortex is composed of a heterogenous population of cells
that give rise to different cell types. The majority of these cells are
derived from radial glia migration that form the different cell types of the neocortex and it is a period associated with an increase in neurogenesis.
Similarly, the process of neurogenesis regulates lamination to form the
different layers of the cortex. During this process there is an
increase in the restriction of cell fate that begins with earlier progenitors giving rise to any cell type in the cortex and later progenitors giving rise only to neurons
of superficial layers. This differential cell fate creates an
inside-out topography in the cortex with younger neurons in superficial
layers and older neurons in deeper layers. In addition, laminar neurons
are stopped in S or G2 phase
in order to give a fine distinction between the different cortical
layers. Laminar differentiation is not fully complete until after birth
since during development laminar neurons are still sensitive to
extrinsic signals and environmental cues.
Although the majority of the cells that compose the cortex are
derived locally from radial glia there is a subset population of neurons
that migrate from other regions. Radial glia give rise to neurons that are pyramidal in shape and use glutamate as a neurotransmitter, however these migrating cells contribute neurons that are stellate-shaped and use GABA as their main neurotransmitter. These GABAergic neurons are generated by progenitor cells in the medial ganglionic eminence (MGE) that migrate tangentially to the cortex via the subventricular zone. This migration of GABAergic neurons is particularly important since GABA receptors
are excitatory during development. This excitation is primarily driven
by the flux of chloride ions through the GABA receptor, however in
adults chloride concentrations shift causing an inward flux of chloride
that hyperpolarizespostsynaptic neurons.
The glial fibers produced in the first divisions of the progenitor cells
are radially oriented, spanning the thickness of the cortex from the ventricular zone to the outer, pial surface, and provide scaffolding for the migration of neurons outwards from the ventricular zone.
At birth there are very few dendrites
present on the cortical neuron's cell body, and the axon is
undeveloped. During the first year of life the dendrites become
dramatically increased in number, such that they can accommodate up to a
hundred thousand synaptic connections with other neurons. The axon can develop to extend a long way from the cell body.
Asymmetric division
The first divisions of the progenitor cells are symmetric, which duplicates the total number of progenitor cells at each mitotic cycle.
Then, some progenitor cells begin to divide asymmetrically, producing
one postmitotic cell that migrates along the radial glial fibers,
leaving the ventricular zone, and one progenitor cell, which continues to divide until the end of development, when it differentiates into a glial cell or an ependymal cell. As the G1 phase of mitosis
is elongated, in what is seen as selective cell-cycle lengthening, the
newly-born neurons migrate to more superficial layers of the cortex. The migrating daughter cells become the pyramidal cells of the cerebral cortex. The development process is time ordered and regulated by hundreds of genes and epigenetic regulatory mechanisms.
Layer organisation
Human cortical development between 26 and 39 week gestational age
The layered structure of the mature cerebral cortex is formed during development. The first pyramidal neurons generated migrate out of the ventricular zone and subventricular zone, together with reelin-producing Cajal–Retzius neurons, from the preplate. Next, a cohort of neurons migrating into the middle of the preplate divides this transient layer into the superficial marginal zone, which will become layer I of the mature neocortex, and the subplate, forming a middle layer called the cortical plate.
These cells will form the deep layers of the mature cortex, layers five
and six. Later born neurons migrate radially into the cortical plate
past the deep layer neurons, and become the upper layers (two to four).
Thus, the layers of the cortex are created in an inside-out order. The only exception to this inside-out sequence of neurogenesis occurs in the layer I of primates, in which, in contrast to rodents, neurogenesis continues throughout the entire period of corticogenesis.
Cortical patterning
Depicted
in blue, Emx2 is highly expressed at the caudomedial pole and
dissipates outward. Pax6 expression is represented in purple and is
highly expressed at the rostral lateral pole. (Adapted from Sanes, D.,
Reh, T., & Harris, W. (2012). Development of the Nervous System (3rd ed.). Burlington: Elsevier Science)
The map of functional cortical areas, which include primary motor and visual cortex, originates from a 'protomap', which is regulated by molecular signals such as fibroblast growth factorFGF8 early in embryonic development.
These signals regulate the size, shape, and position of cortical areas
on the surface of the cortical primordium, in part by regulating
gradients of transcription factor expression, through a process called cortical patterning. Examples of such transcription factors include the genes EMX2 and PAX6. Together, both transcription factors form an opposing gradient of expression. Pax6 is highly expressed at the rostral lateral pole, while Emx2 is highly expressed in the caudomedial pole. The establishment of this gradient is important for proper development. For example, mutations
in Pax6 can cause expression levels of Emx2 to expand out of its normal
expression domain, which would ultimately lead to an expansion of the
areas normally derived from the caudal medial cortex, such as the visual cortex. On the contrary, if mutations in Emx2 occur, it can cause the Pax6-expressing domain to expand and result in the frontal and motor cortical regions enlarging. Therefore, researchers believe that similar gradients and signaling centers next to the cortex could contribute to the regional expression of these transcription factors.
Two very well studied patterning signals for the cortex include FGF and retinoic acid. If FGFs are misexpressed in different areas of the developing cortex, cortical patterning is disrupted. Specifically, when Fgf8 is increased in the anterior pole, Emx2 is downregulated and a caudal
shift in the cortical region occurs. This ultimately causes an
expansion of the rostral regions. Therefore, Fgf8 and other FGFs play a
role in the regulation of expression of Emx2 and Pax6 and represent how
the cerebral cortex can become specialized for different functions.
Rapid expansion of the cortical surface area is regulated by the amount of self-renewal of radial glial cells and is partly regulated by FGF and Notch genes. During the period of cortical neurogenesis and layer formation, many higher mammals begin the process of gyrification, which generates the characteristic folds of the cerebral cortex. Gyrification is regulated by a DNA-associated protein Trnp1 and by FGF and SHH signaling.
Evolution
Of all the different brain regions, the cerebral cortex shows the largest evolutionary variation and has evolved most recently. In contrast to the highly conserved circuitry of the medulla oblongata,
for example, which serves critical functions such as regulation of
heart and respiration rates, many areas of the cerebral cortex are not
strictly necessary for survival. Thus, the evolution of the cerebral
cortex has seen the advent and modification of new functional
areas—particularly association areas that do not directly receive input
from outside the cortex.
A key theory of cortical evolution is embodied in the radial unit hypothesis and related protomap hypothesis, first proposed by Rakic. This theory states that new cortical areas are formed by the addition of new radial units, which is accomplished at the stem cell
level. The protomap hypothesis states that the cellular and molecular
identity and characteristics of neurons in each cortical area are
specified by cortical stem cells, known as radial glial cells, in a primordial map. This map is controlled by secreted signaling proteins and downstream transcription factors.
Function
Some functional areas of cortex
Connections
The cerebral cortex is connected to various subcortical structures such as the thalamus and the basal ganglia, sending information to them along efferent connections and receiving information from them via afferent connections.
Most sensory information is routed to the cerebral cortex via the
thalamus. Olfactory information, however, passes through the olfactory bulb to the olfactory cortex (piriform cortex). The majority of connections are from one area of the cortex to another, rather than from subcortical areas; Braitenberg
and Schüz (1998) claim that in primary sensory areas, at the cortical
level where the input fibres terminate, up to 20% of the synapses are
supplied by extracortical afferents but that in other areas and other
layers the percentage is likely to be much lower.
Cortical areas
The whole of the cerebral cortex was divided into 52 different areas in an early presentation by Korbinian Brodmann. These areas known as Brodmann areas, are based on their cytoarchitecture but also relate to various functions. An example is Brodmann area 17 which is the primary visual cortex.
In more general terms the cortex is typically described as comprising three parts: sensory, motor, and association areas.
Sensory areas
Motor and sensory regions of the cerebral cortex
Motor and sensory regions of the cerebral cortex
The sensory areas are the cortical areas that receive and process information from the senses. Parts of the cortex that receive sensory inputs from the thalamus are called primary sensory areas. The senses of vision, hearing, and touch are served by the primary visual cortex, primary auditory cortex and primary somatosensory cortex respectively. In general, the two hemispheres receive information from the opposite (contralateral) side of the body.
For example, the right primary somatosensory cortex receives
information from the left limbs, and the right visual cortex receives
information from the left visual field. The organization of sensory maps in the cortex reflects that of the corresponding sensing organ, in what is known as a topographic map. Neighboring points in the primary visual cortex, for example, correspond to neighboring points in the retina. This topographic map is called a retinotopic map. In the same way, there exists a tonotopic map in the primary auditory cortex and a somatotopic map in the primary sensory cortex. This last topographic map of the body onto the posterior central gyrus has been illustrated as a deformed human representation, the somatosensory homunculus,
where the size of different body parts reflects the relative density of
their innervation. Areas with much sensory innervation, such as the
fingertips and the lips, require more cortical area to process finer
sensation.
Motor areas
The
motor areas are located in both hemispheres of the cortex. The motor
areas are very closely related to the control of voluntary movements,
especially fine fragmented movements performed by the hand. The right
half of the motor area controls the left side of the body, and vice
versa.
Two areas of the cortex are commonly referred to as motor:
Dorsolateral prefrontal cortex, which decides which voluntary movements to make according to higher-order instructions, rules, and self-generated thoughts.
Just underneath the cerebral cortex are interconnected subcortical masses of grey matter called basal ganglia
(or nuclei). The basal ganglia receive input from the substantia nigra
of the midbrain and motor areas of the cerebral cortex, and send signals
back to both of these locations. They are involved in motor control.
They are found lateral to the thalamus. The main components of the basal
ganglia are the caudate nucleus, the putamen, the globus pallidus, the substantia nigra, the nucleus accumbens, and the subthalamic nucleus. The putamen and globus pallidus are also collectively known as the lentiform nucleus, because together they form a lens-shaped body. The putamen and caudate nucleus are also collectively called the corpus striatum after their striped appearance.
Association areas
Cortical areas involved in speech processing.
The association areas are the parts of the cerebral cortex that do
not belong to the primary regions. They function to produce a meaningful
perceptual experience of the world, enable us to interact effectively, and support abstract thinking and language. The parietal, temporal, and occipital lobes - all located in the posterior part of the cortex - integrate sensory information and information stored in memory. The frontal lobe
or prefrontal association complex is involved in planning actions and
movement, as well as abstract thought. Globally, the association areas
are organized as distributed networks.
Each network connects areas distributed across widely spaced regions of
the cortex. Distinct networks are positioned adjacent to one another
yielding a complex series of interwoven networks. The specific
organization of the association networks is debated with evidence for
interactions, hierarchical relationships, and competition between
networks.
In humans, association networks are particularly important to
language function. In the past it was theorized that language abilities
are localized in Broca's area in areas of the left inferior frontal gyrus, BA44 and BA45, for language expression and in Wernicke's areaBA22,
for language reception. However, the processes of language expression
and reception have been shown to occur in areas other than just those
structures around the lateral sulcus, including the frontal lobe, basal ganglia, cerebellum, and pons.
Clinical significance
Hemodynamic
changes observed on gyrencephalic brain cortex after an arterial vessel
occlusion in IOS. The video has a speed of 50x to better appreciate the
spreading depolarization
over the brain cortex. Pictures are dynamically subtracted to a
reference picture 40 s before. First we see the initial are of change at
the exact moment where the middle cerebral artery group (left) is
occluded. The area is highlighted with a white line. Later we appreciate
the signal produced by Spreading Depolarizations. We see markedly the
front of waves. https://doi.org/10.1007/s00701-019-04132-8
Neurodegenerative diseases such as Alzheimer's disease and Lafora disease, show as a marker, an atrophy of the grey matter of the cerebral cortex.
Brain damage from disease or trauma, can involve damage to a specific lobe such as in frontal lobe disorder, and associated functions will be affected. The blood-brain barrier that serves to protect the brain from infection can become compromised allowing entry to pathogens.
The developing fetus is susceptible to a range of environmental factors that can cause birth defects and problems in later development. Maternal alcohol consumption for example can cause fetal alcohol spectrum disorder. Other factors that can cause neurodevelopment disorders are toxicants such as drugs, and exposure to radiation as from X-rays. Infections can also affect the development of the cortex. A viral infection is one of the causes of lissencephaly, which results in a smooth cortex without gyrification.
A type of electrocorticography called cortical stimulation mapping is an invasive procedure that involves placing electrodes
directly onto the exposed brain in order to localise the functions of
specific areas of the cortex. It is used in clinical and therapeutic
applications including pre-surgical mapping.
Mutations in EMX2, and COL4A1 are associated with schizencephaly, a condition marked by the absence of large parts of the cerebral hemispheres.
History
In 1909, Korbinian Brodmann
distinguished different areas of the neocortex based on
cytoarchitectural difference and divided the cerebral cortex into 52
regions.
Rafael Lorente de Nó, a student of Santiago Ramon y Cajal identified more than 40 different types of cortical neurons based on the distribution of their dendrites and axons.
Other animals
The cerebral cortex is derived from the pallium, a layered structure found in the forebrain of all vertebrates.
The basic form of the pallium is a cylindrical layer enclosing
fluid-filled ventricles. Around the circumference of the cylinder are
four zones, the dorsal pallium, medial pallium, ventral pallium, and
lateral pallium, which are thought respectively to give rise to the neocortex, hippocampus, amygdala, and olfactory cortex.
Until recently no counterpart to the cerebral cortex had been
recognized in invertebrates. However, a study published in the journal Cell in 2010, based on gene expression profiles, reported strong affinities between the cerebral cortex and the mushroom bodies of the ragwormPlatynereis dumerilii.
Mushroom bodies are structures in the brains of many types of worms and
arthropods that are known to play important roles in learning and
memory; the genetic evidence indicates a common evolutionary origin, and
therefore indicates that the origins of the earliest precursors of the
cerebral cortex date back to the early Precambrian era.
A human neocorticalpyramidal neuron stained via Golgi's method. The apical dendrite extends vertically above the soma (cell body) and the numerous basal dendrites radiate laterally from the base of the cell body.
A
reconstruction of a pyramidal cell. Soma and dendrites are labeled in
red, axon arbor in blue. (1) Soma, (2) Basal dendrite, (3) Apical
dendrite, (4) Axon, (5) Collateral axon.
One of the main structural features of the pyramidal neuron is the conic shaped soma, or cell body, after which the neuron is named. Other key structural features of the pyramidal cell are a single axon, a large apical dendrite, multiple basal dendrites, and the presence of dendritic spines.
Apical dendrite
The
apical dendrite rises from the apex of the pyramidal cell's soma. The
apical dendrite is a single, long, thick dendrite that branches several
times as distance from the soma increases and extends towards the
cortical surface.
Basal dendrite
Basal
dendrites arise from the base of the soma. The basal dendritic tree
consists of three to five primary dendrites. As distance increases from
the soma, the basal dendrites branch profusely.
Pyramidal cells are among the largest neurons in the brain. Both
in humans and rodents, pyramidal cell bodies (somas) average around
20 μm in length. Pyramidal dendrites typically range in diameter from
half a micrometer to several micrometers. The length of a single
dendrite is usually several hundred micrometers. Due to branching, the
total dendritic length of a pyramidal cell may reach several
centimeters. The pyramidal cell's axon is often even longer and
extensively branched, reaching many centimeters in total length.
Dendritic spines
Dendritic spines receive most of the excitatory impulses (EPSPs) that enter a pyramidal cell. Dendritic spines were first noted by Ramón y Cajal in 1888 by using Golgi's method.
Ramón y Cajal was also the first person to propose the physiological
role of increasing the receptive surface area of the neuron. The greater
the pyramidal cell's surface area, the greater the neuron's ability to
process and integrate large amounts of information. Dendritic spines are
absent on the soma, while the number increases away from it.
The typical apical dendrite in a rat has at least 3,000 dendritic
spines. The average human apical dendrite is approximately twice the
length of a rat's, so the number of dendritic spines present on a human
apical dendrite could be as high as 6,000.
Growth and development
Differentiation
Pyramidal specification occurs during early development of the cerebrum. Progenitor cells are committed to the neuronal lineage in the subcortical proliferative ventricular zone (VZ) and the subventricular zone (SVZ). Immature pyramidal cells undergo migration to occupy the cortical plate, where they further diversify. Endocannabinoids (eCBs) are one class of molecules that have been shown to direct pyramidal cell development and axonal pathfinding. Transcription factors such as Ctip2 and Sox5 have been shown to contribute to the direction in which pyramidal neurons direct their axons.
Early postnatal development
Pyramidal cells in rats have been shown to undergo many rapid changes during early postnatal
life. Between postnatal days 3 and 21, pyramidal cells have been shown
to double in the size of the soma, increase in length of the apical
dendrite by fivefold, and increase in basal dendrite length by
thirteenfold. Other changes include the lowering of the membrane's resting potential, reduction of membrane resistance, and an increase in the peak values of action potentials.
Signaling
Like
dendrites in most other neurons, the dendrites are generally the input
areas of the neuron, while the axon is the neuron's output. Both axons
and dendrites are highly branched. The large amount of branching allows
the neuron to send and receive signals to and from many different
neurons.
Pyramidal neurons, like other neurons, have numerous voltage-gated ion channels. In pyramidal cells, there is an abundance of Na+, Ca2+, and K+
channels in the dendrites, and some channels in the soma. Ion channels
within pyramidal cell dendrites have different properties from the same
ion channel type within the pyramidal cell soma. Voltage-gated Ca2+ channels in pyramidal cell dendrites are activated by subthreshold EPSPs and by back-propagating action potentials. The extent of back-propagation of action potentials within pyramidal dendrites depends upon the K+ channels. K+ channels in pyramidal cell dendrites provide a mechanism for controlling the amplitude of action potentials.
The ability of pyramidal neurons to integrate information depends
on the number and distribution of the synaptic inputs they receive. A
single pyramidal cell receives about 30,000 excitatory inputs and 1700
inhibitory (IPSPs)
inputs. Excitatory (EPSPs) inputs terminate exclusively on the
dendritic spines, while inhibitory (IPSPs) inputs terminate on dendritic
shafts, the soma, and even the axon. Pyramidal neurons can be excited
by the neurotransmitterglutamate, and inhibited by the neurotransmitter GABA.
Firing classifications
Pyramidal
neurons have been classified into different subclasses based upon their
firing responses to 400-1000 millisecond current pulses. These
classification are RSad, RSna, and IB neurons.
RSna
pyramidal neurons, or non-adapting regular spiking neurons, fire a train
of action potentials after a pulse. These neurons show no signs of
adaptation.
IB
IB pyramidal neurons, or intrinsically bursting neurons, respond to threshold pulses with a burst of two to five rapid action potentials. IB pyramidal neurons show no adaptation.
Function
Corticospinal tract
Pyramidal neurons are the primary neural cell type in the corticospinal tract.
Normal motor control depends on the development of connections between
the axons in the corticospinal tract and the spinal cord. Pyramidal cell
axons follow cues such as growth factors to make specific connections.
With proper connections, pyramidal cells take part in the circuitry
responsible for vision guided motor function.
Cognition
Pyramidal
neurons in the prefrontal cortex are implicated in cognitive ability.
In mammals, the complexity of pyramidal cells increases from posterior to anterior
brain regions. The degree of complexity of pyramidal neurons is likely
linked to the cognitive capabilities of different anthropoid species.
Pyramidal cells within the prefrontal cortex appear to be responsible
for processing input from the primary auditory cortex, primary
somatosensory cortex, and primary visual cortex, all of which process
sensory modalities. These cells might also play a critical role in complex object recognition within the visual processing areas of the cortex.
