Cytoarchitecture of cerebral cortex

Pyramidal cells

Pyramidal cells make up to 75% of the cellular component of the cortex and they are the main output neurons of the cerebral cortex. They vary in size, going from small to gigantic. They usually have one apical dendrite that courses towards the surface of the cortex, and multiple basal dendrites. The number of basal dendrites varies widely, but generally there are more than three to four primary dendrites which branch off to the next generations of dendrites (secondary, tertiary etc) which arborize in the vicinity of the cell body. Usually, they have one long axon that leaves the cortex and enters the subcortical white matter. These axons are destined to be: 

• Commissural that form corpus callosum
• Association that project to the ipsilateral association cortical areas
• or projection fibers which leave the cortex and project to different regions of the CNS, such as the thalamus, spinal cord etc.

Fusiform cells

Fusiform cells are usually placed in the deepest cortical layer. Their dendrite projects towards the cortical surface, whereas the axon also has the possibility to be commissural, association or projection oriented.  Nevertheless, they are usually projection with the biggest odds to project to the thalamus.

Stellate (granular) cells

Stellate (granular) cells are usually small, and since their processes projects in all planes, they resemble a star. They are located all over the cortex, except for the most superficial layer. Their processes are very short and project locally in the cortex, with the role to modulate the activity of other cortical neurons. Based on whether their dendrites have dendritic spines (small cytoplasmic protrusions), they are referred to as spiny cells or aspiny cells. Dendrites of spiny cells do have spines and they are mostly placed within the layer IV where they release glutamate, which is an excitatory neurotransmitter, so they are functionally excitatory interneurons. Aspiny cells release gamma-aminobutyric acid (GABA) which is the most potent inhibitory neurotransmitter of the CNS, so they function as inhibitory interneurons.

Horizontal cells

Horizontal cells of Cajal-Retzius are only seen in the most superficial part of the cortex. They are very rare, and only a few can be found in the adult brain. They have one axon and one dendrite, both of them synapsing locally within the most superficial layer.

Cells of Martinotti

The cells of Martinotti are multipolar neurons that are most densely located within the deepest layer of the cortex. Their numerous axons and dendrites course towards the surface of the cortex.

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Molecular (plexiform)

This is the most superficial layer, laying directly under the pia mater of the the meninges. This layer is very poor with cellular component, which is represented by only a few horizontal cells of Cajal-Retzius. The major portion of this layer is actually the processes of the neurons lying within the deeper layers and their synapses.
 
Most of the dendrites originate from the pyramidal and fusiform cells, whereas the axons are actually the ending fibers of the afferent thalamocortical tract that originates from nonspecific, intralaminar and midline thalamic nuclei.

External granular

This layer consists mostly of stellate cells. The existence of these small cells in this layer gives that “granular” appearance to this layer, hence its name. Other cellular structures are in a form of small pyramidal cells.

Cells of this layer send their dendrites to various layers of the cortex, especially the molecular layer, whereas their axons travel deeper to the cortex synapsing locally. Besides that intracortical synapsing, axons of this layer can be long enough to form the association fibers that travel through the white matter to finally end in the different structures of the CNS.

External pyramidal

The external pyramidal layer consists predominantly of the pyramidal cells. The superficial cells of this layer are smaller than the deeper layer, that is very large.

The apical dendrites of these cells extend superficially and reach the molecular layer, whereas the basal processes join the subcortical white matter and then project again to the cortex, so they serve as both association and commissural corticocortical fibers.

Internal granular

This layer is the main input cortical station (meaning that most of the stimuli from the periphery, arrive here), and for that reason, it is specially developed within the sensory areas.

It consists mostly of the stellate cells and a smaller portion of the pyramidal cells. The axons of the stellate cells remain in the cortex and synapse locally, whereas the axons of the pyramidal cells synapse deeper within the cortex, or they leave the cortex and join the white matter fibers.
 
Stellate cells, as the dominant cellular component, contribute to the formation of specific sensory cortical areas. Those areas receive fibers mostly from the thalamus in the following order:

• Stellate cells of the primary sensory cortex receive fibers from the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei of the thalamus
• Primary visual cortex receives fibers from the lateral geniculate nucleus
• Stellate cells from primary auditory cortex receive projections from the medial geniculate nucleus

When these sensory fibers “penetrate” the cortex, they turn horizontally so they can spread and diffusely synapse with the cells of the internal granular layer. Since these fibers are myelinated and therefore white, they are clearly seen in the environment of the gray matter. This stripe of the white matter is called the outer stripe of Baillarger. Since the stripe is grossly prominent in the primary visual cortex, it is referred to as the stripe of Gennari to make it distinctive.

Internal pyramidal

This layer consists predominantly of the medium-sized and large pyramidal cells. It is the source of the output or corticofugal fibers. For that reason, it is most prominent within the motor cortex from which it sends fibers that mediate motor activity. The primary motor cortex contains a specific form of these cells, called the cells of Betz.
 
Since we’re speaking about the cortical level of motor activity, these fibers form tracts that synapse with different subcortical motor centers. The names of these corticofugal tracts are very suggestive when you are trying to remember the exact place of their ending:

• Corticotectal tract that reaches the midbrain tectum
• Corticorubral tract that goes all the way to the red nucleus
• The corticoreticular tract which synapses with the reticular formation of the brainstem
• Corticopontine tract synapsing with the pons
• The corticonuclear tract that synapses with the motor nuclei in the medullary pyramid
• The corticospinal tract which goes to the spinal cord

This layer also contains a horizontally oriented stripe of the white matter which is called the outer stripe of Baillarger. It is formed by the axons of the internal pyramidal layer that synapse locally within the layer, and also with the cells of the layers II and III.

Multiform (fusiform)

This is the deepest layer of the cortex that directly overlies the subcortical white matter. It contains mostly fusiform cells with less dominant pyramidal cells and interneurons.
 
The axons of the fusiform and pyramidal cells of this layer distribute corticocortical commissural fibers and corticothalamic projection fibers that end in the thalamus.

Overview of the architecture

Each column has its supragranular and infragranular part. 

The supragranular part is made of the most superficial layers I-III, and in general, this part projects to the other columns while at the same time it receives reciprocal connections from them. Specifically, layer III communicates with the adjacent columns, whereas layer II communicates with the distant cortical columns. The infragranular part consists layers V and VI. It receives inputs from the supragranular portions of the adjacent columns and sends outputs to the thalamus.

Layer IV is not functionally included in neither one of these two parts of the column. It is observed as some sort of the anatomical border between the supragranular and infragranular layer, whereas from a functional aspect it has many functions. This layer receives inputs from the thalamus and sends signals to the rest of the belonging column. 

The thalamus, on the other hand, receives info from the almost entire cortex and many subcortical areas. With these connections, the thalamus creates a feedback circuit with the cortex by analyzing the information received from the layer IV, and sending the proper signals back to it. So the integration of the signals occurs both in the thalamus and the cortical centers.

The conclusion is that the supragranular portion mediates the information flow of the cortex, while additional information from the extracortical (mostly) but also other intracortical centers is integrated by the thalamus and sent to the layer IV.

Columnar information processing

Each column can be partially or fully activated. Partial activated column implies that the supragranular layers are excited, whereas the infragranular layers are inactive. When both portions are excited, that means that the column is fully activated.

A level of activation reflects a specific level of function. When a column is fully activated, it corresponds to an action. For example, if the column is within the motor cortex, infragranular layers send signals to the groups of neurons that provoke the contraction of the muscle fibers.

On the other hand, a partially activated motor column corresponds to the state of anticipation or searching, and waits for the infragranular portion to become active. For instance, you are looking for a pen on your desk, your arms are steady and ready, and once you spot it, you execute the movement of taking the pen.

Columnar automaton and problem solving

An automaton is the ability of columns to choose an action based on its current state and the nature of the input signals it receives.  This ability is important for proper problem solving. The problem solving process within the columns can be compared to the same process in the Artificial Intelligence. In that manner of speaking, each column has to:

1. Set the goal and initiate the state necessary to reach that goal
2. Define a set of possible actions that allow the change from one state to another
3. Define the intermediate subgoals (points needed to be reached in the process of the accomplishing the final goal)
4. Finally reach the goal from the initial state by accomplishing the intermediate subgoals, coming closer to the final goal each time.

Now, we know that the classical problem solving is sequential. But different from that, the cerebral cortex operates in a parallel mode compared to the problem solving. This means that at any point in time, the cortex can handle multiple problems while setting multiple goals and defining multiple initial states with the simultaneous and interdependent activations of different numbers of cortical columns. 

When a goal is defined, the wave of excitation spreads along the supragranular layers. Afterwards, the infragranular layer is stimulated and in that way the column becomes fully active, which then effects extracortical action. This extracortical action modifies the environment and thus changes the new thalamic inputs. As a result, other columns which have up to now been supragranularly activated, but have not yet received the right thalamic inputs, become fully activated. The process continues until the original goal becomes fully activated. Many goals will be under progress simultaneously within the cortex. The spreading activations and sub-actions are always interacting and interfering with each other.

Connections of the columns

Based on the nature of the information, these connections can be specified as afferent, and efferent.

Afferent connections

These connections mostly originate from the thalamus, brainstem, and hypothalamus. Based on the type of the neurotransmitter, these connections can be cholinergic, noradrenergic, dopaminergic or serotonergic. All of them synapse diffusely through the cerebral cortex.
 
Most of these afferents come from thalamus and they travel to the cortex through the thalamocortical radiations. Based on from which exact thalamic nuclei they originate, these fibers are referred to as specific or non-specific.

• Specific thalamocortical fibers end within layers III and IV of the cerebral cortex, synapsing with stellate and pyramidal cells. The most important specific thalamocortical fibers are actually axons of the second neurons of all of the sensory tracts except for the olfactory pathway.
• Non-specific fibers send collateral branches to all of the cortical layers and then end within layer II.

Efferent connections

They are mostly the axons of the pyramidal cells. Before they leave the cortex, those axons send collateral branches that form cortico-cortical connections. As said before, efferent fibers are:

• Associative that usually originate from the neurons of layers II and III of the cortex.
• Commissural fibers arise in layers III and IV of one cerebral hemisphere and cross the midline to terminate in the corresponding cortical area of the contralateral hemisphere
• Projection fibers arise from layers V and VI. Fibers from layer V synapse with specific motor nuclei within the brainstem to innervate their motor neurons, whereas those from layer VI project to the thalamus in a form of the corticothalamic tract.

Motor cortex

This cortical area contains:

• Primary motor cortex that is located in the precentral gyrus of the frontal lobe (Brodmann’s area 4) and is essential for the execution of voluntary movements
• Secondary motor cortex that consists of the four regions:
  • Supplementary motor cortex
  • The premotor cortex
  • The frontal eye field
  • The posterior parietal motor area

Primary motor cortex is located anterior to the central sulcus and is presented with the Brodmann's area 4. It contains anterior two-thirds of the paracentral lobule, and then it spreads through precentral gyrus, narrowing ventrally towards lateral sulcus.

Many parts of this field are responsible for the voluntary movements of certain body parts. The arrangement of the primary motor cortex is somatotopic, which means that specific groups of muscles are innervated by specific groups of neurons. That means that these groups of neurons “represent” their muscles. Those groups of neurons give rise to the fibers for specific parts of the corticospinal and corticonuclear pathway.
 
Fibers from the paracentral lobule innervate muscles of the foot and shin. On the medial edge of the hemisphere is the field that represents the muscles of the thigh, while ventrally the representation fields for the muscles of the abdomen, thorax, arm, head, and neck are aligned. The size of these areas does not correspond to the size of the body parts they represent, but to the complexity of the movements that those muscles can produce. For that reason, the representation field of the muscles of the hand is bigger than for the other groups of the muscles of the arm. Schematic representation of the body parts in a way they are represented in the cortex gives an image of minimized and deformed man, called motor homunculus.

Rostrally to the inferior part of the primary motor cortex, motor speech area (Broca area) is located. It is placed within the part of the inferior frontal gyrus and is represented with Brodmann's area 44 and 45, and with the most human brains, it is located within the left hemisphere.
Lesions of this area cause motor aphasia, a condition when the patient knows what he wants to say, but his speech is incomprehensible.
 
The premotor area (Brodmann’s area 6) strips rostrally to the primary motor area on the lateral surface of the hemisphere. Part of this area is located on the medial surface of the hemisphere, and that part is called supplementary area. The premotor cortex is essential for planning of the movements. It sends that information to the primary motor cortex, which then starts the execution of the movement.
 
The frontal eye field is placed in the posterior part of the medial frontal gyrus ( Brodmann’s area 8). It has a significant role in the movements of the eye bulb.

Sensory cortex

The sensory cortex contains several very important areas:

• Primary somatosensory area
• Secondary somatosensory field
• Primary visual field
• Secondary visual field
• Primary acoustic field
• Primary olfactory fields
• Primary gustatory field
• Primary vestibular field

Primary somatosensory area (Brodmann’s 3, 1, 2) is placed within the most of the postcentral gyrus and last third of the paracentral lobule. It receives the fibers of the medial lemniscus, spinothalamic pathway, and trigeminothalamic pathway. All of these axons arise from the ventral posterolateral nucleus of the thalamus.
 
Inside this area there is also somatotopic arrangement. The size of the representational receptive field is proportional to its representation surface within this cortical area. For that reason, the biggest surface is taken by the representational fields of the receptive sensory areas from the hand and face. Mapped schematically, the entire area is represented with sensory homunculus.

The secondary somatosensory area is placed rostrally to the central sulcus, along with its edge. The sensory fibers that conduct nociceptive sensibility (pain) end here.
 
Primary visual area (Brodmann’s area 17 and V1) is the striate area. The biggest portion of this area is placed within the medial aspect of the occipital lobe, and surrounds the calcarine fissure. The neurons of the optical pathway end here. Secondary visual areas (Brodmann’s area 18 and 19) are responsible for identification and understanding of the properties of the observed object.
 
Primary acoustic area (Brodmann's area 41 and 42) is placed in the superior side of the superior temporal gyrus, where there are the so called Heschl gyri. This area has a tonotopic arrangement, meaning that certain parts of cochlea correspond to certain parts of this area. The primary olfactory area is placed within the piriform cortex that is located between the insula and the temporal lobe. Also, the prepiriform cortex is the part of the primary olfactory area, and it is found between the lateral olfactory tract and the temporal cortex.
 
The primary gustatory area is placed within the most inferior parts of the postcentral gyrus and adjacent parts of the insula. The primary vestibular area is thought to be in superior temporal gyrus.

Test your knowledge about the motor and sensory cortical homunculus with our quiz!

Associative cortex

Gathering, multimodal and supramodal integration of the cortical impulses, all are the actions that happen within the associative areas. Supramodal integration is directly connected to gnostic and symbolic functions that are unique to the human brain.
 
One of the most important associative areas is found on the mutual border of the parietal, occipital and temporal lobe. This area contains the supramarginal gyrus (Brodmann’s area 40), the angular gyrus (Brodmann’s area 39) and the posterior part of the superior temporal gyrus (Brodmann’s area 22 - Wernicke field). This cortical area is specifically important for the processes of speech, reading, writing and visual orientation.

On the inferior surface of the temporal lobe, specifically within the lateral occipitotemporal gyrus, is the area for the face recognition. If a patient is suffering from a lesion of this area, they are unable to recognize the faces even of their closest family, just like in that book from Oliver Sacks “The man who mistook his wife for a hat”.
 
The  prefrontal associative area extends through the biggest portion of the frontal lobe (Brodmann’s areas 8, 9, 10, 11, 12, 45 and 46), and it takes up to 25% of the entire cortical surface. This area is divided into lateral, medial and ventral (orbitofrontal) part. It has reciprocal connections with all parts of the CNS, but especially with the hypothalamus and dorsomedial nucleus of the thalamus. This entire area is essential for cognitive thinking, judgment, motivation, emotions, and planning of the behavior.

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Allocortex

This cortex contains most ancient phylogenetically structures placed within the archicortex, which is definitely the eldest, and the paleocortex, that is a bit younger than the archicortex. The archicortex consists of only three cellular layers: polymorphic, pyramidal and the molecular layer. It is associated with the limbic system, specifically with the hippocampal formation, meaning it is involved with emotional expression and memory.

The paleocortex contains three to five layers of cells. It is located within the parahippocampal gyrus (entorhinal cortex), uncus (piriform cortex) and lateral olfactory gyrus, meaning it mediates the sense of smell.

Mesocortex

This is actually the transitional form between the allocortex and isocortex. It contains three to six layers and is found in the insula and cingulate gyrus.

Isocortex (neocortex)

Isocortex is the most recent cortical portion. This cortex makes up to 90% of the human cortex and it makes up all of the lobes except for the limbic. It consists of six layers of cells marked with Roman numbers I to VI, going from the most superficial layer to the deepest:

• the first four layers (I-IV) are input stations that receive corticopetal fibers.
• layers V and VI are output stations that give rise to corticofugal projection fibers.

Due to this functional differences, not all the parts of the cerebral cortex will have all six layers equally developed. For that reason, the motor cortex contains numerous pyramidal cells that are efferent, with the maximum density of them within the layers II-V. On the other hand, granular cells are not that numerous within these layers, so the motor cortex is commonly referred to as the agranular cortex.
 
Unlike the motor cortex, the primary sensory cortex is heavily filled with stellate cells and contains a small portion of the pyramid cells. For that reason, this cortex is also called granular cortex.