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Heterotopias in the Brain: When Neurons Get a Little Lost

I’ve talked a little about heterotopias in the past although I haven’t focused on them considerably. But that’s about to change today because they are fascinating occurrences which happen occasionally within the brain and, if they coincide with some other condition, can often give insight into how the condition developed in the first place. Tuberous Sclerosis is a great example that I’ll touch on later.

What is a heterotopia? This is a term used to describe cells or groups of cells which are migrationally or developmentally misplaced but which still maintain some of the characteristics of the tissue type they were supposed to have been a part of. An excellent example of this is when neurons appear in the white matter tracts of the brain, having failed to migrate properly into the cortex. Frequently, heterotopias are associated with seizure activity, although they also are known to occur in the wider, unaffected general population on occasion without association to any known condition. This is especially true of the nodular type of subcortical heterotopias which will be discussed below.

There are a variety of types of heterotopias that can occur in relation to the neocortex. This may sometimes be individual cells, but more often are seen in larger nodules or full bands of cells or even in ribbon-like arrangements as a semi-separated continuation of the normal cortex. Heterotopias can occur within the subependymal and periventricular (neural stem cell) zone just overlying the ventricles of the brain, and subcortically just beneath the cortical gray matter. The image below is a hemisphere of a normal adult brain to help you visualize where the different heterotopias may occur.


Neuroradiologists tend to divide heterotopias into three main groups, the first two of which can occur either in nodules or larger bands: 1) periventricular/subependymal heterotopias, 2) subcortical heterotopias, and 3) subcortical band heterotopia, as seen in Double Cortex Syndrome. Both periventricular and subcortical forms can occur as either nodular or laminar-like formations, although that has also lead to confusions about the use of “laminar” versus “band” which have been used both interchangeably and distinctly. However, Barkovich and Kjos (1992) state that,

“Radiologically, band heterotopia [as seen in Double Cortex Syndrome] and subcortical heterotopia are distinct. Band heterotopia consist of smooth layers of gray matter that often follow the curvature of the overlying cortex. They are not convoluted nor are they contiguous with the overlying cortex. They do not contain blood vessels or CSF. Subcortical heterotopia usually consist of swirling, heterogeneous, curvilinear masses of gray matter often containing blood vessels and CSF. They are essentially always contiguous with the overlying cortex and the underlying ventricular surface.”

So, basically he suggests that it is better to avoid the use of the term “laminar” altogether, because even though subcortical “laminar” heterotopias may have some sort of laminar or layered appearance, they are less “banded” than the true band heterotopia and do occasionally degrade into a more nodular form. Below is a picture of a subcortical band heterotopia.


Image of a subcortical band heterotopia, borrowed from here.

Many band heterotopias are thought to be associated with genetic conditions, such as the Double Cortex Syndrome mentioned earlier that is frequently associated with a mutation in the DCX gene. The doublecortin gene interacts with the cytoskeleton of newborn neurons, which has the potential to affect all aspects of cell motility, such as growth and migration. A few cases of Double Cortex Syndrome have also been linked with mutations in LIS1, a protein that interacts with doublecortin. Because the condition is X-linked, females with DCX mutations exhibit the more typical subcortical band heterotopia while males exhibit varying grades of lissencephaly or “smooth brain”.

The well-known autism-associated condition, Tuberous Sclerosis, is also typified by heterotopias, specifically within the periventricular area. Rather than exhibiting focalized heterotopias, people with TSC often have multiple nodular heterotopias, as shown in the image below. Most cases of TSC are due to mutations in the TSC1 and TSC2 genes which are negative regulators of the growth-related Akt pathway. As you can imagine, if one of these genes are knocked out, then activity of Akt increases and subsequently increased cellular growth and proliferation ensues.


Image of periventricular heterotopias, borrowed from here.

So those, folks, are heterotopias. Hopefully you’ve found our little neuropathology class interesting and enlightening. To wrap this up, I’d also like to mention that many people with autism whose brains have been studied postmortem present with heterotopias, particularly nodular forms within the cerebellum and cerebrum. So that really suggests proliferation, differentiation, and perhaps even migration may be altered in the heterogeneous condition. Just some food for thought.

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