Introduction

The human brain is a complex and fascinating organ, containing millions of neurons and hundreds of different specialised regions, each with its own important roles and responsibilities. One of these regions, arguably one of the most important, is the cerebral cortex. This region, responsible for higher-order functions such as language, reasoning, and voluntary movement, is distinguished by its highly folded appearance, spanning the entire surface of the brain.¹ However, these folds are not just for show - they also have an important purpose.

However, when the developmental processes that underlie cortical folding are disrupted, the consequences can be profound. One such disruption is observed in lissencephaly, a rare but severe disease which interrupts normal cortical development, characterised by a smooth or nearly smooth brain surface. 

This article explores the typical timeline of cortical folding during prenatal development, the cellular and molecular mechanisms involved, and how this process is impaired in lissencephaly.

Structure and function of the cerebral cortex

The cerebral cortex is the outermost layer of the brain, formed of grey matter involved in sensory processing, motor control, memory, language, and executive functions.

Its characteristic cortical folds, consisting of gyri (the ridges) and sulci (the grooves), dramatically increase the brain surface area, enabling dense packing of neurons within the limited confines of the skull. Cortical folding is a key process of neurodevelopment, emerging during foetal life through a precise and orchestrated sequence of cellular events.

The timeline of cortical folding in typical human development

Human brain development starts just a few weeks after conception and develops throughout gestation. Among these processes, the highly orchestrated and stage-dependent process of cortical folding begins at around 10 weeks and continues into week 40 of gestation. Several factors, such as genetic signals, cellular migration patterns and mechanical forces, influence it.^2,3 Chronological overview of this process is as follows.

Weeks 10–12 (initial cortical development)

In the early second trimester (around 10–12 weeks into pregnancy), the foetal brain looks smooth and undeveloped. This is when neurogenesis begins. Neurogenesis, the process of the neurons (nerve cells) and glia (cells that support nerve cells and have protective functions).

This largely occurs in a specialised location in the brain called the ventricular zone, where neural stem cells begin to multiply in a process called proliferation - the rapid growth and division of cells. These stem cells give rise to mature neurons and glia.

At this point, the cortex is still very thin, just a few layers of cells. There are no folds yet, and the brain is still smooth.³

Weeks 14–20 (neuronal migration and pre-folding)

From approximately week 14, neurons begin to migrate radially from the ventricular zone toward the developing cortex along specialised glial scaffolds. This neuronal migration is essential for establishing the six-layered structure of the neocortex.^2,3

Although the cortex remains largely smooth during this period, its internal architecture is being organised in preparation for later folding. Improper migration during this phase often results in structural abnormalities such as lissencephaly, heterotopias, or polymicrogyria.^2,3

Weeks 20–24 (primary sulcation)

Between weeks 20 and 24, the first primary sulci, which are the major folds in the cortex, begin to appear. These include the Sylvian fissure, central sulcus, and parieto-occipital sulcus, which have distinct and important functions.

These folds occur at consistent anatomical locations and are believed to be genetically programmed.³ Simultaneously, the cortical plate continues to thicken due to further neuron migration and dendritic growth.

Weeks 24–32 (secondary sulcation and elaboration)

The brain begins to take on a more densely folded appearance. Secondary sulci begin to develop during this phase. Increased cortical expansion, especially in the frontal, temporal, and parietal lobes, drives this process.³

Weeks 32 to birth (tertiary folding and refinement)

In the final trimester, the brain undergoes substantial volumetric growth. Tertiary sulci, which are the smallest and most variable folds, form during this period. These folds are often unique to individuals and may underlie aspects of personalised cognitive traits.

By term, the cortex has reached a level of folding comparable to that seen in postnatal life, although brain maturation continues well into adolescence.

Lissencephaly: a disruption in the folding sequence

A disruption in the intricate process of cortical folding can give rise to such diseases as Lissencephaly.

What is lissencephaly?

Lissencephaly is a rare but severe condition in which the brain fails to develop its characteristic folds and grooves. In most cases, the brain may appear almost completely smooth (agyria) or have only a few broad folds (pachygyria). This happens when something disrupts the migration of neurons between weeks 12 and 24 of pregnancy, right when the building blocks of the cortex are supposed to move into place.⁴

What causes lissencephaly?

Genetic mutations are the major causes of lissencephaly.⁴ These are changes to specific genes that guide the development and movement of neurons. Some of the key genes involved include:

• LIS1 (PAFAH1B1), regulates how neurons move along scaffolding inside the brain⁵
• DCX (Doublecortin), which helps stabilise the internal “rail system” that neurons use to reach their destination⁶
• RELN regulates the encoding of the gene ‘reelin’⁷

When these genes are faulty, it’s as if neurons lose their GPS signal. Instead of travelling to the cortex in an organised way, they get lost, pile up in the wrong layers, or fail to move at all. Without this precise layering, the cortex cannot form the folds that normally develop in later stages.

There are two main types of lissencephaly:

1. Type I (Classic lissencephaly): Smooth brain with a thickened cortex and disrupted layering⁴
2. Type II (Cobblestone lissencephaly): The brain surface appears bumpy or pebbled due to neurons migrating too far past the cortex⁴

What are the symptoms?

Because the structure of the brain is so fundamentally altered, the symptoms of lissencephaly can be profound. They include, but are not limited to:

• Seizures (often starting early and difficult to control)
• Severe developmental delays
• Low muscle tone (hypotonia) or spasticity
• Feeding and swallowing difficulties
• Impaired motor skills
• Intellectual disability

The severity of symptoms depends on the affected brain regions.

How is lissencephaly diagnosed?

Doctors often first suspect lissencephaly based on delayed development or seizures in infancy. Diagnosis is confirmed with brain imaging, usually MRI, which can reveal the smooth or simplified brain surface and thickened cortex. Genetic testing is used to identify the underlying mutation, which can help guide treatment and provide information for family planning.

Can it be treated?

There is currently no cure for lissencephaly. Treatment focuses on managing symptoms and improving quality of life. This may include:

• Anti-seizure medications
• Physical, occupational, and speech therapy
• Feeding support, such as gastrostomy tubes
• Mobility aids and special education services

Children with lissencephaly often require lifelong care. In severe cases, life expectancy may be shortened, but some individuals can live into adolescence or adulthood, depending on the degree of brain involvement.

The journey from a smooth foetal brain to a deeply folded adult cortex is a marvel of biological engineering. Each fold represents not just growth, but coordination, as neurons travel vast microscopic distances to form the circuits that power our thoughts, memories, and movements.

With lissencephaly, that journey is interrupted. By understanding how and when things go wrong, researchers are not only working toward better care for affected families but also uncovering the deepest mysteries of how the human brain builds itself from scratch.

Summary

• Cortical folding (the development of grooves and ridges in the brain) starts around week 10 of pregnancy and continues until birth. It allows the brain to fit more neurons into the limited space of the skull, supporting higher functions like thinking, movement, and language
• The folding process follows a precise timeline in which early brain cells are produced in the ventricular zone (weeks 10–12), migrate outward to form brain layers (weeks 14–20), and gradually form larger folds (primary sulci), then smaller ones (secondary and tertiary sulci) from weeks 20 to 40
• Lissencephaly is a rare brain disorder wherein these folds fail to develop properly, resulting in a smooth or underfolded brain. This happens between weeks 12 and 24 of gestation, when neurons can’t migrate to their correct positions
• The condition is often caused by genetic mutations in key genes (LIS1, DCX, and RELN) that control how neurons move and organise themselves during development
• Symptoms of lissencephaly can include seizures, severe developmental delays, muscle weakness, and feeding difficulties. The severity depends on how much of the brain is affected
• While there is no cure, treatment focuses on managing symptoms with therapies, medications, and supportive care. Understanding the condition also allows scientists insight into how the brain builds itself before birth