Embryology of CNS

13 April 2009

Feras Rawagah

Remember that the central nervous system originates from the ectoderm. In the fourth week, the CNS starts to develop. The diagram shows the dorsal surface of the embryo, which is called the ectoderm. The notochord was formed within mesoderm during development. At the midline region which is the axis of embryo, the surface ectoderm called neural plate starts to show invagination, which can be seen as a dorsal groove in the dorsum of embryo. This groove is called the neural groove. As it continues to invaginate towards the axis, it starts to separates itself from the surface. When it is completely separated, it will be completely embedded inside the mesoderm, and the whole surface will be united to form a tube called the neural tube. So, remember: Neural plate >>> Neural fold Neural groove >>> >>> Neural tube Neural canal

All this process is called neurulation = formation of neural tube. Neural tube is designated to form the central nervous system.
From slides: Only small areas remain open at both ends; the lumen of the tube (neural canal) will remain in communication with the amniotic cavity at these openings. These openings are called neuropore (rostral & caudal). Not shown in image!

At the lateral side of the axis, there are modified ectodermal cells that surround the neural plate and neural tube. They are called the neural crest. They will be differentiated into specialized nervous tissue to form the peripheral nervous system. They will be located on the dorsum of neural tube, and then they will separate and migrate bilaterally. Derivatives of neural crest (Tartora): Dorsal root ganglia of spinal nerves Spinal nerves Ganglia of cranial nerves Cranial nerves Ganglia of autonomic nervous system Adrenal medulla Meninges

So: Neural tube Neural crest Neural canal

>>> >>> >>>

Central nervous system Peripheral nervous system Cerebral ventricles & aqueduct & central canal of spinal cord

When the whole system begins to appear, the tube begins to modify. At this age the embryo begins to fold on itself, and begins to produce different systems in the body. The neural tube surrounds a cavity (neural canal) that will develop into ventricles, cerebral aqueduct, and central canal. In the adult, there is a huge part of this cavity called the lateral ventricles (rt. & lt.) present in each cerebral hemisphere bilaterally. They are joined into a single cavity in the midbrain called the third ventricle. Then it continues behind the brain stem as a canal called cerebral aqueduct until reaching the region posterior to the pons and anterior to cerebellum where it enlarges into a diamond shaped cavity called the fourth ventricle. Then it continues to the spinal cord as a narrow canal called the central canal. All these cavity structures are derived from the lumen of neural tube (neural canal). The neural tube is originally divided by flexures or constrictions. The tube is divided into three portions called primary brain vesicles. Then these three vesicles will divide to form five portions called secondary brain vesicles. This means that two primary vesicles divide each into two secondary vesicles while one primary vesicle does not divide. The primary vesicles are called prosencephalon, mesencephalon, and rhombencephalon. Also called forebrain, midbrain, and hindbrain, respectively. Prosencephalon Mesencephalon divides into telencephalon and diencephalon. Rhombencephalon divides into metencephalon and myelencephalon. does not divide (the middle one)

Note below the left image representing the secondary vesicles. Notice structures derived from every part, and the lumen formed by every one (very important)

Neural tube

Prosencephalon (Forebrain)

Mesencephalon (Midbrain)

Rhombencephalon (Hindbrain)

Spinal cord

Telencephalon Cerebral hemispheres Basal ganglia

Diencephalon Thalamus, Hypothalamus Epithalamus, Subthalamus Pineal gland

Mesencephalon Midbrain

Metencephalon Pons Cerebellum

Myelencephalon Medulla oblongata

Spinal cord Spinal cord

Lateral ventricles

Third ventricle

Cerebral aqueduct

Fourth ventricle (upper part)

Fourth ventricle (lower part)

Central canal

This diagram summarizes divisions and derivatives of neural tube memorize them. Note that the portion that does not divide is the middle one; the mesencephalon, and its lumen is the cerebral aqueduct. Diencephalon will form the ventral aspect of the forebrain. It will give rise to thalamus and associated structures and will surround the third ventricle which is between the thalami.

Telencephalon will form the largest portion of the brain (the hemispheres) and will form the largest cavities within the brain (the lateral ventricles); it will grow rapidly and occupy the largest portion of the cranial cavity. Lateral ventricle is the largest ventricle which approaches all the lobes of adult brain. What is the significance of having cerebrospinal fluid inside the ventricles? Support of the brain and shock absorber.

Here we notice the brain vesicles with the structures they form and each one of them surrounds a cavity filled with cerebrospinal fluid. In early age, there is invasion of the surrounding vasculature to the region of the cavity in this flexure (dashed area in the upper big image), where capillaries starts to appear. This vasculature later on gives rise to the choroid plexus. This is the region of lateral ventricles and the third ventricles. So the first production of cerebrospinal fluid is in lateral and third ventricles. Later on we will see it also in the fourth ventricle.
From the slides: The embryonic brain grows rapidly and bends ventrally with the head fold. This will produce three flexures: Midbrain flexure, in the midbrain region. Cervical flexure, at the junction of the hindbrain and spinal cord. Pontine flexure, formed as a result of unequal growth of the brain between the previous flexures. The cervical flexure separates the hindbrain from the spinal cord. The Pontine flexure divides the hindbrain into caudal (myelencephalon) and rostral (metencephalon).

These images also illustrate the rapid enlargement and modification of brain vesicles. The skull occupies half the size of embryo because of this rapid growth and enlargement of the nervous tissue. The most rapid one is the forebrain which forms the cerebrum which occupies most of the cranial cavity. At about the end of embryonic period, the end of eighth week or two months, the shape of the whole flexures will show the appearance of future brain, but it is not a complete one; the ventricles (lumen) is still very large, and the neuronal tissue (wall) are still expanding rapidly. That is, the wall is still thin while the lumen is still big. With time, the wall (neuronal tissue) expands while the lumen (ventricles) narrows. One month later, in the third month, the whole cerebrum will have rapidly been increased in size to show most of the space occupied by developing brain. At about the seventh month, when the fetus is now capable of living independently, the adult shape of the brain is established. The first part to appear is the cerebrum; the last part to appear is the cerebellum. Notice that the cerebrum is evident by the end of embryonic period (the second month), but the cerebellum starts to appear one month later, with the formation of the diamond shape cavity in front of it (the fourth ventricle). Later on the cerebellum will acquire the adult shape, and the cerebrum will occupy most of the cranial cavity.

Layers of embryonic nervous tissue (Tartora)

Three layers of cells differentiate from the neural tube: Outer marginal layer = marginal zone cells develop into white matter. Middle mantle layer = intermediate zone cells develop into gray matter. Inner ependymal layer = ventricular zone cells form the lining of brain ventricles, cerebral aqueduct, and central canal of spinal cord.

Cranial and spinal nuclei and nerves

Along the whole neuronal tube, which begins proximally from the forebrain, and distally to the tail of hindbrain, and spinal cord, the tube will show aggregations of certain neuronal masses (gray matter). We can divide these neuronal aggregations within the neural tube into two parts: Some in the brain region, inside the cranial cavity Some in the spinal cord region, in the vertebral column Aggregations in the spinal cord are just a continuation of that in the brain, but there are differences between two regions, see later. Along the whole cavity of nervous system, the whole tube is constricted at the side and dividing the neuronal material into alar and basal plates. So, the aggregation of these neuronal cells will be disposed into two regions along the whole tube which are the alar plate and the basal plate. The basal plate is the ventral (anterior) one while the alar plate is the dorsal (posterior) one. These two plates will give rise to CNS Nuclei, which will be origins of special nerves emerging from these nuclei formed by the plates. In the brain region (intracranial portion), We call these nerves the cranial nerves, while in the continuation down the spinal cord (intravertebral portion) we call the nerves the spinal nerves. The arrangement is divided into afferent (sensory) and efferent (motor) nuclei. The afferent is formed by the alar plate (the dorsal), while the efferent is formed by the basal plate (the ventral).

So remember: Alar plate Basal plate Dorsal nucleus Ventral nucleus Afferent nerve Efferent nerve sensory motor

This table applies to both the cranial part and the spinal part.

What is the difference between the cranial part (brain) and vertebral part (spinal cord)? In the adult cranial part of CNS, the cortex is of gray matter and the inside is the white matter; that is, the arrangement is: White matter in the center, Gray matter in the periphery. But in the spinal cord, it is inverted: gray matter inside and white matter in the periphery. The origin of these two arrangements (white & gray matters in brain & spinal cord) is established by the arrangement of the alar and basal plates. Alar and basal plates arrange to form the gray matter (nuclei), and according to the place of arrangement, there will be the place of gray matter.

In the cranial part

At early embryonic age (week six), some of the cranial nerves starts to appear. Later on, the rest of the cranial nerves appear. Most of these cranial nerves arise from the anterior aspect of the brain and the brain stem. Trochlear nerve is the only one which arise form the posterior aspect. The earliest cranial nerves to appear are two pure sensory: olfactory & optic nerves. In the cranial part of CNS, there are four afferent nuclei at the alar plate, three efferent nuclei at the basal plate. These are the primordia of special fibers contained by each cranial nerve. So, there are the seven masses forming the cranial nerves as follows: Alar plate Basal plate 4 3 Dorsal nuclei Ventral nuclei Afferent fibers Efferent fibers

In the spinal part

In the spinal cord, the issue is a continuation of the brain. Each spinal nerve is formed by a dorsal sensory root derived from alar plate and a ventral motor root derived from the basal plate. The roots exit from the dorsal and ventral horns of gray matter in the spinal cord. So, same principle as cranial part, there are many masses along the spinal cord forming the spinal nerve as follows: Alar plate Basal plate Dorsal root nucleus (Dorsal horn) Afferent (sensory) Efferent (motor) Ventral root nucleus (ventral horn)

Now we take a section of neural tube in details- the image here is a section of spinal cord, we discuss sections in general.

If we take a section of neural tube in any region, and study the structure of neuronal cells found in the wall which will form adult structure, we can differentiate tree zones: Special cells towards the cavity (lumen) called ventricular zone The largest middle portion is the intermediate zone or mantle zone Cell on the periphery called the marginal zone These were discussed above. We notice also in the section that the lumen becomes narrower with time while the wall tissues are expanding. In cranial part, gray matter occupies the cortical region and white matter is pushed towards the middle. According to doctor, marginal zone is responsible for the formation of the cortex! In case of spinal cord, we notice the modification within the alar and basal nuclei; we notice how they differentiate into ventral and dorsal roots in all regions, and lateral roots in some regions_ but not all regions have lateral roots. And we notice how the periphery will form the fibers of white matter.

Positional changes of the spinal cord

The spinal cord, as a continuation of hindbrain, runs through the vertebral canal of vertebral column. While the time the spinal cord is growing, the vertebrae derived from the surrounding mesoderm is also growing. The vertebrae ossify later on, and form the vertebral canal. The notochord remains as a mass between the two; spinal cord and vertebral canal. At the beginning, until the end of embryonic period, the spinal cord occupies the whole vertebral canal, approaching down to the lowest sacral vertebra, even to the coccygeal peace of sacrum. Later on, the growth of vertebral column becomes more rapid than the growth of nervous tissue of spinal cord.

A 8w B 24w C newborn D adult

The result is: the vertebral column becomes longer than the spinal cord. Still in the intrauterine life, in the sixth month, the spinal cord reaches the level of S1. This means it has been regressed. But the connection with lower vertebrae remains through a structure called filum terminale which extends contained within pia mater to the coccygeal piece of sacrum. At birth, in newborn, the spinal cord has regressed to the lowest portion of L3, but it is still longer than that of adult. In adult, the spinal cord terminates below the L1. These are important for clinical practice for performing lumbar puncture. All the process of regression occurs because the growth of vertebral column is faster than that of spinal cord.

Development of coverings
From the beginning, the whole neural tube including prosencephalon, mesencephalon, rhombencephalon, and its continuation to the spinal cord, is surrounded by a membrane; the meninges. The coverings also develop and show modifications. Development of Meninges (from Before We Are Born): The mesenchyme surrounding neural tube condenses to form primordial meninx. Outer layer of it form the dura mater. Internal layer gives rise to the framework of leptomeninges (arachnoids & pia maters). Then, the framework of leptomeninges is invaded by cells from neural crest. In the same time, the whole cranial wall is also approaching and ossifying its components. The bone pieces approach each other until they meet to form sutures at the junctions between them. However, some parts of the cranial cavity remain membranous (the fontanels) to allow further growth of the brain without pressing on it. Later on, these membranous parts also will ossify to form the complete bony box, which is the skull.

Congenital anomalies
The whole process of development may not complete properly, giving rise to developmental abnormalities.

Anencephaly
A process in which neither the skull nor the brain will develop; that is no skull and no brain. So, the whole structure will be opened. In this case, the child probably will not complete the pregnancy.

Microcephaly
A process in which the process of development and enlargement of brain and skull is stopped at a certain point. The child here will be born alive with small brain and skull.

Hydrocephaly
Normally, cerebrospinal fluid starts to be secreted early in the development, and filtrated through some foramina; foramen of Moro, foramen of Majindi etc. Sometimes, these foramina will be closed for certain reason, and this leads to accumulation of the cerebrospinal fluid. This is called hydrocephaly.

Spina bifida
It is a common abnormality. Occurs when the vertebra surrounding the spinal canal is not ossified completely; that is, the region of the spinous process of a vertebra is not ossified. The result might be exposure of the spinal cord.

In one type of spina bifida, present in large number of normal people, the vertebral arch is not completely ossified, but there is no protrusion, and the appearance of the back is normal. This is called spina bifida occulta; occulta = hidden or silent. Usually people do not complain about it, and it could be discovered incidentally by X-Ray for any other purpose. According to some books, 10% of normal population have this anomaly. So, usually we consider it normal. Other variants of spina bifida are serious: In one variant, the whole vertebral arch is not formed, and the meninges with their circulating cerebrospinal fluid are bulging outside the vertebral column; this is called meningocele. It is usually in the lumbar region. In the most serious variant, the whole spinal cord is pushed outside the vertebral column, this is called miningomyelocele.

These are varieties of abnormalities. Some of them are very serious, which are usually associated with other serious abnormalities, which we see only after the death of the newborn. So, abnormalities are either within the developing neuronal tube, or in the circulating fluid, or the surrounding skull and vertebral column.

The End

Evolutionary basis of some diseases

The nature created selective pressures for inducing evolution on a period of hundreds of millions of years of alternative processes of variation and selection. This has build up our genetic setup to adapt these pressures of wild life medium. The central nervous system human has continued to evolve until reaching a degree of having communication skills and higher thinking enough for forming societies and inventing new methods of gaining life.

One of the main invented methods of life is the change from the life of gaining food by hunting and picking up fruits, to the life of producing food by agriculture and growing up animals. This change occurred before about twelve thousand years. At that point, the environmental media changed massively around human being. But, twelve thousand years is not enough for producing significant evolution enough to completely adapt for these changes and to overcome the effect of the former hundreds of millions of years of evolution in the wild life. So, our genetic setup is still adapted for the wild life, and not completely adapted for modern life. The vast change in life style without enough simultaneous change in our genetic setup to accommodate this style is the basis of many modern human chronic diseases. Examples are obesity, diabetes mellitus, and hypertension. Obesity. Mammals in general have constant body temperature which is essential for normal metabolism and survival. This means that in winter, when the weather is cold, the body requires more energy to fix body temperature at a constant level. But in winter in the wild life, food is rare, so there is no enough energy for survival. This fact requires an accommodation for storage of any extra energy gained during summer, when there is plenty of food, and to preserve it for winter, when it is required. This adaptation is accomplished by building adipose tissue for energy storage and by stimulation of appetite to take any extra food available. This is very important for survival in the wild life. In modern life, however, there is no need for this adaptation, because the human solved the problem of food shortage in winter by inventing methods for preserving food, such as drying, cooling, etc. furthermore, the problem of cold weather is solved by invention of clothes and warming methods. However, although the need of that adaptation is not present in modern life, the adaptation is still present; our bodies are still managing extra food in the same way, and our nervous system is still stimulating our appetite in the same way. This incompatibility between our old genetics and our modern life created the problem of obesity. Hypertension. The wild life is dangerous and requires rapid response to danger by modifying all body systems functions to encounter the danger. This response is mediated by stress, which stimulates the sympathetic nervous system to affect all body systems. One of the major responses is to increase blood pressure, as an anticipation to increase blood flow to muscles whenever there is a need to attack or escape. Stress in the wild life is associated with condition that requires muscle activity to survive; for example, to escape from a lion. So, increased blood pressure in stressful condition is very important for survival in wild life. In modern life, however, stress is associated with condition that does not imply a danger requiring muscular activity and increased blood pressure, such as routine stresses of our jobs. However, the response to these conditions is the same_ increased blood pressure. Why? This is because stress is nonspecific response and has not adapted to be specific for each stimulus in a different way. This is because modern life is new, and our genetics has not evolved to make stress specific for our modern life. This incompatibility between our old genetics and our modern life could be the basis of hypertension. Diabetes mellitus. Before invention of agriculture, the human consumption of carbohydrates was minimal, and our genetics was accommodated to manage only this amount of carbohydrates. This is because the main food was gained by hunting, which contains mainly proteins and lipids with little amounts of carbohydrates. After invention of agriculture, however, the carbohydrates became the main source of energy in human food. However, our genetics is still somehow adapted to accommodate low amounts of carbohydrates, and the human has not evolved enough to accommodate the large amounts of carbohydrates consumed in the modern life. This incompatibility could be the origin of diabetes mellitus, the disease of carbohydrate metabolism. Written by: Feras Rawagah