Brain development (Biological Aspects 4)

The human brain weighs 1.3 kg and is made up of 100 billion neurons with 100 trillion connections.

It is thought to have ten times a many glial cells as neurons.

It is one of the most the most complex structures in the known universe. 

Not extraordinary in “absolute” terms

• During the course of our development, humans build big brains, but there are animals that develop bigger brains than ours:

• The elephant has a brain 3.5 bigger than human’s.

• The Blue Whale’s brain is 5 times bigger than ours (Passingham 1982). 

Encephalisation Quotient (EQ)

Big bodies require big brains. If one is interested in brain processing over and above body control, one must factor out the effect of body size. The EQ is calculated according to the expected brain size for an average mammal of a given body size.

Actual brain size

- divided by - 

Average brain size for a mammal of that body weight 

Human EQ = 7.5.

Hence, we have a brain 7.5 times bigger than one would expect of an average mammal of our body size (Jerison 1973) 

Primates as an Order have relatively bigger EQs than other types of animals.

Our brain is 3.1 times as big as one would expect for an average primate of our body size

•   Thus, in absolute terms humans do not build the biggest brains on the planet during the course of development. Nevertheless, it is a much bigger brain than one would expect for an average mammal, or even primate, of our body size.

•   Our brain size has a profound effect upon all aspects of our development across our lifespan. 

[see diagram of life cycle of hunter gatherers compared to other groups]

In general, animals with big bodies develop slowly.

• However, even when we allow for body size primates develop particularly slowly compared to other mammals.

• The rate of development is correlated with adult brain size. 

Length of Gestation in Primates

P  - 126 days

OWM - 168 days 

GA  - 238 days

H - 266 days (see different lengths for each in chart)

The length of gestation is determined by the size of brain that needs to be built. However, by such logic, our gestation should last 3 times longer than a chimpanzee’s: i.e., 714 days or 24 months! 

Brain capacity at birth (compared to adult):

• Rhesus macaque 60% • Chimpanzee 46% • Human beings 23% 

In humans the brain continues to grow at the foetal rate for two years after birth (Bogin 1997):

By 3 year of age it is at 80% adult capacity and 90% by five years of age (Dekaban & Sadowsky 1978) 

BRAIN WEIGHT:

• Newborn's brain: about 25% of adult size

• Age 3: about 80% of adult size

• Age 5: about 90% of adult size 

Early postnatal pattern of brain development:

• Brain size estimated at 330 cubic centimetres, about the same as a 3 year-old chimpanzee.

• However, compared to the adult values of its species, the Dikika baby had formed only between 63 and 88% of the adult brain size, which is lower than that of a 3 year only chimpanzees whereby over 90% of the brain is formed.

• This relatively slow brain growth observed in A. afarensis is slightly closer to that of humans, pointing to a possible behavioural shift in this species (Science Daily 2006). 

• It is not just in terms of brain size that we seem underdeveloped at birth:

• –  Human beings seem to be born before they are fully developed. Our bones do not fully calcify until one year after birth.

• –  Rhesus macaques have a gestation period of 24 weeks, their bones have fully calcified by the 18th week of gestation.

• • Humans develop a very large brain and yet because of bipedal locomotion the female of the species has a long and narrow birth canal.

  • Hence rather than waiting, we push our babies out early.

• It is very tight squeeze!

• Size of neonate’s head relative to the pelvic outlet (compare diagram):

  Spider monkey v Orangutan v Proboscis monkey v Macaque v Gibbon v Chimp v Gorilla v Human

• At the points where the plates of the skull meet are little gaps called fontanelles. The anterior fontanelle in newborn humans is a diamond shaped aperture of an inch in diameter. It allows the bones to slide over each other slightly reducing the dimensions of the cranium during birth.

• The cranial plates do not grow together until about 2 year of age.

• There must have been intensive selection pressure for large brain in humans, which seems to have started early... 

One cell to trillions

•   All human life starts with one cell: the fertilized egg or zygote. How can a single cell be responsible for such wondrous complexity?

•   A zygote contains the blueprint for our brains and body. Each is comprised of 23 pairs of chromosomes. Each chromosome is packed full of long strands of DNA, which can be divided into functional units called genes.

• Gene-environment interaction

  • Although brain development is “gene-driven”, there is also a vital interaction with environment factors.

  • All aspects of development are the result of an interaction between genes and the environment. The development of the brain constitutes an interplay between biologically inherited processes and environmental influences (Smith et al. 2003).

Encephalisation

[see diagrams]

In humans, the cephalic (head) portions of the neural tube grow tremendously and this disproportionate growth is referred to as “encephalisation”.

Even before closure of neural tube is complete, the cephalic part of the neural tube differentiates into 3 primary spaces, or ventricles. 

By 5 weeks, the first and third of these divide once more forming a series of five ventricles which will become the major portions of the central nervous system within the skull (Hochstetter 1919).

One of the most sensitive periods in brain development occurs at the very beginning, when the neural tube is closing.

• Anencephaly literally means a lack of cerebral cortex. The neural tube fails to close at anterior (or front) end and babies are born with no brain. The condition is always fatal.

• Spina bifida is caused by a failure of the neural tube to close properly at posterior (rear) end so that part of the spinal cord develops outside the spine, rendering it vulnerable to damage. The condition has varying outcomes. 

After the first five weeks, the brain’s gross features are formed by growth and flexion (or bending) of the neural tube’s anterior (front) portions. The result is a cerebral cortex that envelops the subcortical and brainstem structures that started out in line with the cortex along the neural tube. The final gross structural form are the product of continued cortical enlargement and folding. 

Stage 1: Cell Birth

Neurones are the information super highways of the brain.

By 7 months of human gestation nearly all of the adult number of 100 billion neurones have been produced.

To produce this number, about 250,000 neurones must be born PER MINUTE at the peak of brain development. Yet the newborn brain is less than a quarter the adult brain volume or weight. Where do you think the extra volume comes from? 

Postnatal brain volume comes from:

►Synaptogenesis - formation of new synapses ►Myelination of many axons (glial cells) ►Increased branching of dendrites

Neuron and Glial Formation

The neural tube is the “nursery” for the brain and its cells.

The cells that line the neural tube are neural stem cells.

Stem cells line the ventricles – the ventricular zone. These cells have an extensive capacity for renewal. They give rise to progenitor or precursor cells. 

Stem cell switch points: Neuroblast to glioblast production

At early stages, a stem cell generates neuroblasts. Later, it undergoes a specific “switch point” at which it changes from making neurons to making glia. 

Stage 2: Cell Migration

 Radial glia transform into astrocytes in the adult brain. Astrocytes perform many functions including providing structural support, insulation, and carrying nutrients.

Stage 2: Growth Cones

Growth cones dynamically crawl forward dragging the rest of the axon behind them. Their extension is controlled by cues in their outside environment that ultimately direct them toward their appropriate synaptic targets.

The fine threadlike extensions are filopodia, which find adhesive surfaces and pull the growth cone and therefore the growing axon in a particular direction. 

Cortex built from the inside out

• First neurons lie in the deepest cortical layers, whereas the last to migrate push through them to the cortical surface (building up the layer of an onion).

• Six cortical layers are constructed, but at different rates in different parts of the brain 

Disruption of cortical development

• Anything that disrupts the normal timeline of cortical construction has profound effects on cortical formation.

• Neuronal migration is severely disrupted by chronic maternal alcohol abuse resulting in fetal alcohol syndrome with cognitive, emotion and physical disabilities.

Stage 3: Cell Differentiation

• For the first 5-6 weeks cell division in the ventricular zone is symmetrical – every cell is the same (a precursor cell)

• From 5-6 weeks onwards there is asymmetrical division

  – cell divides, 1 migrates, 1 remains in ventricular zone; cycle repeats

Cell determination

The type of cell a migratory neuron becomes and the location it ends in is determined by gestational age at cell division.

Neurons born at the same age migrate to prespecified cortical layer regardless of whether they remain in the donor (their original cellular environment) or are transplanted to an older host (R) 

Stage 4: Cell Maturation

 Once a neuron has reached its final position, it grows out its axons and dendrites.

 “Exuberant growth”: transient innervation of cells / areas not connected in adult

divergence: 1 cell innervates more cells than it does in adult. Extra connections eliminated through develop

Stage 4: Cell Maturation

 Cell grows axon, dendrites

 “Exuberant growth”: transient innervation of cells / areas not connected in adult

convergence: several neurons innervate one target neuron. Eventually only one neuron innervates. 

Stage 5: Synaptogenesis

Axons (with growth cones on end) form a synapse with other neurons or tissue (e.g. muscle) 

Synaptogenesis: Attraction to Target Cells

Target cells release a chemical that creates a gradient (dots or crosses in diagrams) around them.

Growth cones orient to and follow the gradient to the cells.

The extensions visible in the far right picture are growing out of a sensory ganglion (left) toward their normal target tissue (right). 

Stage 6: Neuronal Death

•Between 40% and 75% of all neurons born in embryonic and fetal development do not survive.

•They fail to make optimal synapses.

•Use it or lose it!

Neuronal death leads to Stage 7 - Synaptic rearrangement

Release and uptake of neurotrophic factors

Neurons receiving insufficient neurotropic factor die

Axonal processes compete for limited neurotrophic factor 

Stage 7: Synapse Rearrangement

• Active synapses likely take up neurotrophic factor that maintains the synapse

• Inactive synapses get too little trophic factor to remain stable

Synesthesia

• Synesthesia is a neurological condition in which stimulation of one sensory or cognitive pathway leads to automatic, involuntary experiences in a second sensory or cognitive pathway. There are many kinds, e.g.:

  – Color-graphemic synesthesia, letters or numbers are perceived as inherently colored

  – Visual motion → sound synesthesia involves hearing sounds in response to visual motion and flicker

• There is a hypothesis that at least some kinds of synesthesia is due to an unusual pattern or cell death or dendritic pruning during development 

Stage 8: Myelination 

Myelination Lasts for up to 30 Years

Learn diagram 

The influence of genes

At least half of our genome is devoted to producing our brain.

For the nine months of intrauterine life and for a short but indeterminate postnatal period, brain growth and development will be largely genetically determined.

Recent advances in molecular genetics have identified numerous genes that are expressed in the developing brain and that control CNS development. 

Epigenetic (environmental) factors

• –  involved from beginning

• –  play increasingly important role

• –  cell death, synaptic shedding, synaptic rearrangement and myelination all take place during and after foetal development. The number and kinds of connections that are established and survive are related to environmental input. 

Plasticity

Postnatal development

•   There is some neuronal plasticity (after all cell death, synaptic shedding, synaptic rearrangement and myelination all startbefore but continue after birth)

•   this plasticity is limited. Cells are not free to migrate to new areas, or to make large changes in long-distance connectivity

  Sensitive periods

•  extrinsic influences can alter brain organisation

•  once sensitive periods pass lack of plasticity

  Adult CNS damage

•  irreversible
   neurons don’t regenerate damaged connections

   lost neurons not replaced (although Eriksson et al. 1998 found new neurons produced in the adult hippocampus) 

Postnatal development: Synaptic shedding

At birth At six At 14 years years (diagrams)

The degree and exact pattern of synaptic shedding is influenced by environmental input. 

Example:

Diamond et al (1987)

Rats kept in enriched physical and social environment had more dendritic connections (9,400 compared to 7,600) that were thicker than control rats kept in impoverished environments.

Example:

Sensitive periods: Environmental impoverishment of Romanian orphan

• 1989: Fall of Communist regime

  • –  1000s of severely deprived children from state orphanages

  • –  Many adopted in USA, Canada, UK, other European countries

• Investigationofconsequencesof deprivation, ‘sensitive periods’ in cognitive, language, social development

Example: Romanian Orphans:  Those children adopted at less than 4 months of age were found to have an IQ of 98 at 4.5 years

►Those adopted at a median of 19 months had an IQ of 90 at 4.5

►Age matched Canadian control children had an IQ of 109 (at 4.5 years)

Example:

Sensitive Periods: Weisel & Hubel (1965)

One of a kitten’s eyes was sown shut for the first 4-6 weeks of life.

After the stitches were taken out the cells that would usually process visual information were unable to do so. After this sensitive period sewing the eyes shut has no effect.

Visual development needs environmental input during a sensitive period of neural development. 

Example:

Visual deprivation in human development

Amblyopia (lazy eye) – vision deficiency in an eye that is otherwise normal. There are several causes such as a drooping eyelid or one eye turned inward (strabismus)

• –  requires surgical correction

• –  if uncorrected by 7-8 years, pattern vision is almost

  completely suppressed and individuals can be

  functionally blind in the affected eye

• –  no adaptation with subsequent correction 

Plasticity in the adult brain

• Adult humans learn ... learning involves changes in synaptic weights between neurons. So, there must be functional plasticity in the adult brain.

• ›  How great is the change?

• ›  How much is there cortical reorganisation?

• New neurons in the adult hippocampus

  • Eriksson et al. (1998) found that new neurons were produced in the adult hippocampus.

  • Maguire et al. (2000) found that London taxi drivers who had completed “The Knowledge” had enlarged hippocampuses compared to non-taxi drivers. It is impossible to tell whether the enlargement was principally due to dendritic proliferation or neurogenesis. 

  • Mike Merzenich and his colleagues have shown how cortical sensory and motor maps can be modified with experience.

  • The somatosensory map is a point by point representation of sensory areas

  • More sensitive areas are larger & more densely packed

  • Adjacent areas in body are adjacent on somatosensory map 

  (see examples, incl)
  

• • Male adult, left arm amputated

  • When areas of his face were touched with a Q

    tip, he reported sensations in various areas of the left hand and arm. This is different to phantom limb sensation - where you feel as if your arm is still there independently of any stimulation.

  • Essentially there was now a map of the young man’s hand on his face. This is because the areas of the somatosensory cortex responsible for the left hand/arm had been taken over by those adjacent areas – the head/face. There is now overlap such that sensation can be triggered from the ‘new’ source to the older, now nonexisting (amputated) limb.

    Ramachandran 1993 

Conclusions

•   Developmental neurobiology is a rapidly growing field of research

•   The brain has a profound effect on the pattern of human development across the lifespan

•   There is a precise timing of cortical development

•   The brain undergoes exuberant proliferation and then fine tunes its connections

•   There is some plasticity, particularly in prenatal brain during sensitive periods and some plasticity is now known to exist in adults