Smooth Brains: Causes and Neurological Consequences

The human brain’s surface is typically covered in folds, known as gyri and sulci, which increase its surface area and enhance cognitive function. However, in some cases, the brain develops with an unusually smooth structure, a condition known as lissencephaly. This rare neurological disorder leads to significant developmental delays, motor impairments, and seizures, underscoring the importance of cortical folding in normal brain function.

Folding Patterns In The Cerebral Cortex

The intricate folding of the cerebral cortex, characterized by gyri (ridges) and sulci (grooves), allows for a significant expansion of surface area without requiring a larger skull. The degree of folding varies across species, with primates and cetaceans exhibiting highly convoluted cortices, while rodents and smaller mammals have relatively smoother brains. A greater surface area accommodates more neurons and synaptic connections, supporting advanced cognitive functions.

Folding results from mechanical forces and cellular processes during fetal development. The tension-based model suggests that differential growth rates between cortical layers create mechanical stress, leading to buckling and the emergence of gyri and sulci. MRI studies and computational modeling indicate that regions with higher neuronal connectivity fold inward as sulci, while less constrained areas protrude outward as gyri. Additionally, intermediate progenitor cells in the subventricular zone influence cortical thickness and complexity, with disruptions in these populations linked to abnormal folding patterns.

Molecular signaling pathways also regulate cortical organization. Genes such as LIS1, DCX, and TUBB2B are crucial for neuronal migration, ensuring neurons reach their correct locations. Mutations in these genes cause lissencephaly, where the absence or reduction of folds results in a smooth cortex. Signaling molecules like fibroblast growth factors (FGFs) and sonic hedgehog (SHH) influence cortical expansion by modulating progenitor cell proliferation and differentiation. Disruptions in these pathways can lead to excessive folding, as seen in polymicrogyria, or a near-complete lack of folds, as seen in lissencephaly.

Developmental Pathways Affecting Cortical Gyrification

Cortical folding is guided by genetic, molecular, and biomechanical factors that shape brain development from early embryogenesis. Neural progenitor cells proliferate and migrate, establishing the framework for gyrification. Disruptions in these processes can result in excessive convolution or a nearly smooth cortex.

Neural progenitor cell populations in the ventricular and subventricular zones play a central role. Radial glial cells, which serve as scaffolds for migrating neurons, generate progenitors that contribute to cortical thickness and surface area. The balance between symmetric and asymmetric cell division determines neuron availability for cortical expansion. Genes such as ARHGAP11B, unique to humans, enhance basal progenitor proliferation, increasing cortical folding. In contrast, mutations in LIS1 and DCX disrupt neuronal migration, preventing gyrification and leading to lissencephaly.

Growth factors and extracellular matrix components also shape cortical architecture. FGFs and SHH signaling regulate progenitor proliferation, ensuring proper cortical layer expansion. Disruptions in these pathways can cause hypergyrification or a near-complete absence of folds. The extracellular matrix, including proteins like laminin and reelin, provides structural support and guidance for neuronal positioning. Mutations in RELN, which encodes reelin, have been linked to severe cortical malformations, including lissencephaly with cerebellar hypoplasia.

Mechanical forces refine the folding process. Computational models and imaging studies suggest that regions with higher neuronal connectivity experience increased tangential expansion, forming gyri, while areas under less tension develop into sulci. Observations across species with varying gyrification levels support this tension-based hypothesis. The interplay between mechanical stress and molecular signaling ensures cortical folds develop to optimize neural connectivity and cognitive function.

Neurological Effects Of Smooth Brain Structure

The absence of typical cortical folding in lissencephaly significantly alters brain function, leading to widespread neurological impairments. A smooth cortex reduces surface area for neuronal connections, limiting information processing. Affected infants often exhibit hypotonia, feeding difficulties, and delayed motor milestones. Cognitive development remains severely impaired, with most individuals experiencing profound intellectual disability and difficulty performing complex tasks.

Seizures are a major consequence, often emerging in the first months of life. Many individuals develop infantile spasms or drug-resistant epilepsy due to abnormal neuronal organization and disrupted synaptic connectivity. The irregular distribution of excitatory and inhibitory neurons contributes to hyperexcitability, making seizure control difficult. EEG studies frequently reveal chaotic, high-amplitude waveforms indicative of widespread cortical dysfunction. Standard antiepileptic treatments provide limited relief, often requiring a combination of medications, dietary therapy, and, in some cases, surgical interventions such as vagus nerve stimulation.

Motor function is also severely affected due to impaired communication between the cortex and subcortical structures. Many individuals with lissencephaly exhibit spasticity, dystonia, or profound hypotonia, interfering with voluntary movement and coordination. These deficits stem from disrupted corticospinal tract development, impairing the brain’s ability to send precise signals to muscles. Speech and language abilities are severely restricted, with most individuals remaining nonverbal or developing only rudimentary communication skills. Assistive technologies, including eye-tracking devices and alternative communication systems, can sometimes improve interaction, but outcomes vary widely.

Genetic Underpinnings And Role Of Progenitor Cells

Proper cortical folding depends on a tightly regulated genetic framework controlling neural progenitor cell behavior. Mutations in LIS1, DCX, and TUBA1A disrupt progenitor proliferation, migration, and differentiation, leading to lissencephaly. LIS1, located on chromosome 17p13.3, encodes a protein essential for microtubule stabilization and intracellular transport, guiding neurons to their correct cortical positions. Loss-of-function mutations impair radial glial scaffold integrity, causing neurons to stall in deeper cortical layers. Similarly, DCX, an X-linked gene, encodes doublecortin, a protein critical for neuronal migration. Mutations in DCX cause classical lissencephaly in males and a milder form, subcortical band heterotopia, in females due to X-inactivation.

Basal radial glial cells (bRGCs) play a crucial role in gyrification by generating intermediate progenitors that expand the cortical plate. Human-specific genes such as ARHGAP11B increase bRGC proliferation, a process absent in lissencephalic brains. Studies using cerebral organoids derived from induced pluripotent stem cells (iPSCs) show that introducing ARHGAP11B into non-gyrified species, such as ferrets, induces additional cortical folds, highlighting the gene’s role in human brain expansion. Disruptions in progenitor populations not only reduce cortical thickness but also limit the formation of essential neural circuits, profoundly affecting cognitive and motor function.