Lost in Migration: Exploring the Roots of Grey Matter Heterotopia

Written By Dimple Kangriwala

Dimple Kangriwala 

Illustrations by Stewart Heintz

Have you ever lost a package in the mail? If you have, it was probably at the most inconvenient moment possible. Maybe it was a textbook you needed to study for an upcoming exam, or a prop necessary for a play you were putting on. You might have checked the UPS tracking constantly, refreshing and refreshing, waiting for it to arrive. When delivery day finally arrived, you sat by the window, invented reasons to walk by the door, and peered outside your home at every rumble of an approaching car. But no luck: it just never showed up. Little did you know, your package had been delivered to another doorstep — all the way across the city. Say this package was a bunch of neurons you needed to construct an area of your brain. Without these cells, your brain would not be able to function properly. This misplacement of neurons within the brain is known as grey matter heterotopia (GMH), with heterotopia translating to "out of place." Simply put, during neural development, neurons may not migrate to their predetermined destination and instead end up in an area where they do not belong [1].

The Trials and Tribulations of Neural Development

Grey matter gets its name from the many grey-colored neurons in the outermost layer of the brain, known as the cerebral cortex. These cells are vital components of the brain, playing a major role in cognition, memory, emotion, and behavior [2]. Grey matter cells in the cerebral cortex interact with other parts of the brain to aid in higher-level processing, which includes decision-making and analysis of sensory input. Changes to these cells and their organization can disrupt neural activity and communication, hindering the overall functioning of the brain [3]. Grey matter heterotopia (GMH) is one such change to the organization of these grey matter cells, where neurons end up in the wrong place during neural development. 

Normal neural development can be broken down into three steps: neural proliferation, cell migration, and cell differentiation. During neural proliferation, neural precursor cells, which are destined to develop into a specific type of neural cell (in this case, grey matter neurons), prepare to begin their journey across the brain [2]. Think of these precursor cells as cars on a highway. Just as drivers are guided by signs on a highway, precursor cells are guided by the projections of supporting cells to help them reach their final destination [4]. Every driver has their own map to follow, and every precursor cell has genetic programming that directs it to a specific location in the brain. Genetic programming also tells the cell to take on a characteristic appearance that corresponds to that specific neuron’s location and function, a process called differentiation [2]. Differentiation can occur well before the precursor cell reaches its final destination, meaning these cells know what kind of neural cells they will become before their journey comes to an end [2]. Though the cells aren’t fully differentiated when they’re migrating, they have already been prepared to become a certain type of neuron — neurons designated for the cerebral cortex are akin to vacationers prepared for a warm beach villa. These vacationers may have brought nothing but swimming trunks and flip-flops for their journey, so if they take a wrong turn on their road trip and end up at a freezing ski resort, they would be woefully unprepared. In the same way, grey matter neurons that end up in the wrong place in the brain can cause disastrous effects. In GMH, where migration goes awry, neural precursors fail to reach their destination, resulting in neurons differentiating in unintended areas. This is a problem, because if a differentiated neuron is in an area where it is not supposed to be, it cannot function properly in its new environment, leading to neural communication errors.

Wrinkles: A Person’s Fear, the Brain’s Frontier

During migration, a neuron receives instructions from its genes, like a map that instructs it on how to reach its intended destination [5]. Some vital information on this map can be missing, like in a genetic condition called DiGeorge’s Syndrome (DGS), which is one cause of grey matter heterotopia. In DGS, some of the directions on the genetic map are deleted, causing the neuron to migrate to an undesignated location. This faulty migration can have a staggering impact on brain development, causing grey matter heterotopia and resulting in a range of the physical and psychological symptoms associated with DGS [5]. Since DGS causes a large amount of grey matter cells to end up in the wrong location, it not only limits migration, but also the process of gyrification — the process where the brain creates its wrinkly pattern of bumps and grooves [6]. These folds are important because they increase the surface area of the cerebral cortex, enabling a greater number of neurons to interact. Reduced folding hinders short range neuronal connectivity, which may result in the development of ADHD, seizures, or anxiety disorders [7, 8]. In short, DGS can lead to grey matter heterotopia, which in turn lowers cerebral cortex volume, resulting in changes to brain structure and function due to improper distribution of neurons [9–12]. 

The Reality of It All: GMH and Schizophrenia 

If a neuron is misdirected by a deletion on its genetic “map,” the consequences can also be psychological, not just structural. One well-studied psychiatric disorder that occurs alongside GMH is schizophrenia, a mental disorder that is characterized by delusions, hallucinations, and disturbances in thoughts and perception [13, 14]. The causes of schizophrenia vary, and may include genetic factors and abnormalities in neurotransmission, though in some cases the exact cause cannot be explained [15, 16, 17]. Many studies have investigated genetic components, namely DiGeorge’s Syndrome, to explore this correlation between GMH and schizophrenia [5, 8, 18, 19, 5]. DGS is present in 1–2% of schizophrenia cases, despite being present in less than 0.1% of the entire population, suggesting a causal relationship between the two conditions [20, 21, 5]. Moreover, people with schizophrenia, whether they’re born with or without DGS, show lower grey matter volume than people without schizophrenia [22, 23, 20]. This disparity implies that reduced amounts of grey matter is indeed a characteristic of schizophrenia, thereby demonstrating the connection between the disorder and GMH. Reductions in grey matter impact neural connectivity, which can also contribute to symptoms of schizophrenia [24].


A Crash Course in Course Correction 

The abnormal migrations of grey matter neurons suggest a startling connection to schizophrenia. The connection between GMH and schizophrenia can open new avenues for research, paving the way for novel therapies targeting these disorders. As of now, there is no clear treatment for GMH itself, but there are treatments for the disorders and symptoms produced by GMH [25, 26]. By treating schizophrenia with a variety of medications and therapies, doctors can reduce symptoms, but they cannot target the underlying cause [27]. Targeting GMH as an underlying contributor could lead to progress in the discovery of new treatments for schizophrenia [27]. Further research is needed to establish a better understanding of GMH and its connection to genetics, as it can open new doors to gene therapy research and techniques. New treatments could give these beach-bound neurons a corrected map to follow so that they can reach their sunny destination and have the relaxing vacation they prepared for.

References

  1. Zając-Mnich, M., Kostkiewicz, A., Wiesław, G., Dziurzyńska-Białek, E., Solińska, A., Stopa, J., & Kucharska-Miąsik, I. (2014). Clinical and morphological aspects of gray matter heterotopia type developmental malformations. Polish Journal of Radiology, 79, 502–507. doi:10.12659/PJR.890549

  2. Bear, M. F., Connors, B.W., & Paradiso, M.A. (2015). Neuroscience: Exploring the brain (4th ed.). Wolters Kluwer Health

  3. Mercadante, A. A., & Tadi, P. (2022). Neuroanatomy, Gray Matter. StatPearls Publishing. PMID: 31990494

  4. Rahimi-Balaei, M., Bergen, H., Kong, J., & Marzban, H. (2018). Neuronal migration during development of the cerebellum. Frontiers in cellular neuroscience, 12, 484. doi:10.3389/fncel.2018.00484

  5. Meechan, D. W., Maynard, T. M., Tucker, E. S., & LaManita, A. S. (2010). Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: Patterning, proliferation, and mitochondrial functions of 22q11 genes. International Journal of Developmental Neuroscience, 29(3), 283–294. doi:10.1016/j.ijdevneu.2010.08.005

  6. Serevino, M., Geraldo, A. F., Utz, N., Tortora, D., Pogledic, I., Klonowski, W., Triulzi, F., Arrigoni, F., Mankad, K., Leventer, R. J., Mancini, G. M. S., Barkovich, J.A., & Lequin, M. H. (2020). Definitions and classification of malformations of cortical development: Practical guidelines. Brain, 143(10), 2874–2894. doi:10.1093/brain/awaa174

  7. Vasung, L., Rezayev, A., Yun, H.J., Song, J. W., van der Kouwe, A., Stewart, N., Palani, A., Shiohana, T., Chouinard-Decorte, F., Levman, J., & Takahashi, E. (2019). Structural and diffusion MRI analyses with histological observations in patients with lissencephaly. Frontiers in Cellular Developmental Biology, 7, 124. doi:10.3389/fcell.2019.00124

  8. Zinkstok, J. R., Boot, E., Bassett, A. S., Hiroi, N., Butcher, N. J., Vingerhoets, C., Vorstman, J. A. S., & van Amelsvoort, T. A. M. J. (2019). Neurobiological perspective of 22q11.2 deletion syndrome. Lancet Psychiatry, 6(11), 951–960. doi:10.1016/S2215-0366(19)30076-8

  9. Thompson, C. A., Karelis, J., Middleton, F. A., Gentile, K., Coman, I. L., Radoeva, P. D., Mehta, R., Fremont, W. P., Antshel, K. M., Faraone, S. V., & Kates, W. R. (2017). Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 174(3), 295–314. doi:10.1002/ajmg.b.32515

  10. Drobinin, V., van Gestel, H., Zwicker, A., MacKenzie, L., Cumby, J., Patterson, V. C., Vallis, E. H. Campbell, N., Hajek, T., Helmick, C. A., Schmidt, M. H, Alda, M., Bowen, C. V., & Uher, R. (2020). Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness. Journal of Psychiatry and Neuroscience, 45(2), 125–133. doi:10.1503/jpn.180144

  11. Dufour, F., Schaer, M., Debanné, M., Farhoumand, R., Glaser, B., & Eliez, S. (2008). Cingulate gyral reductions are related to low executive functioning and psychotic symptoms in 22q11.2 deletion syndrome. Neuropsychologia, 46(12), 2986–2992. doi:10.1016/j.neuropsychologia.2008.06.012

  12. Kiehl, T. R., Chow, E. W. C., Mikulis, D. J., George, S. R., & Bassett, A. S. (2009). Neuropathologic features in adults with 22q11.2 deletion syndrome. Cerebral Cortex, 19(1), 153–164. doi:10.1093/cercor/bhn066

  13. Lippi, G. (2017). Neuropsychiatric symptoms and diagnosis of grey matter heterotopia: A case-based reflection. South African Journal of Psychiatry, 23, 923. doi:10.4102/sajpsychiatry.v23i0.923

  14. The American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text revision). American Psychiatric Association Publishing. doi:10.1176/appi.books.9780890425787

  15. Picchioni, M. M., & Murray, R. M. (2007). Schizophrenia. British Medical Journal, 335(91). doi:10.1136/bmj.39227.616447.BE

  16. Rahman, T., & Lauriello, J. (2016). Schizophrenia: An overview. Focus, 14(3), 300–307. doi:10.1176/appi.focus.20160006

  17. Howes, O. D., McCutcheon, R., Owen, M. J., & Murray, R. M. (2017). The role of genes, stress, and dopamine in the development of schizophrenia. Biological Psychiatry, 81(1), 9–20. doi:10.1016/j.biopsych.2016.07.014

  18. Ramanathan, S., Mattiaccio, L. M., Coman, I. L., Botti, J. C., Fremont, W., Faraone, S. V., & Antshel, K. M., Kates, W. R. (2017). Longitudinal trajectories of cortical thickness as a biomarker for psychosis in individuals with 22q11.2 deletion syndrome. Schizophrenia Research, 188, 35–41. doi:10.1016/j.schres.2016.11.041

  19. Schaer, M., Debanné, M., Cuadra, M. B., Ottet, M., Glaser, B., Thiran, J., & Eliez, S. (2009). Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): A cross-sectional and longitudinal study. Schizophrenia Research, 115(2-3), 182–190. doi:10.1016/j.schres.2009.09.016

  20. Karayiorgou, M., Simon, T. J., & Gogos, J. A. (2010). 2q11.2 microdeletions: Linking DNA structural variation to brain dysfunction and schizophrenia. Natural Reviews Neuroscience, 11(6), 402–416. doi:10.1038/nrn2841

  21. The International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237–241. doi:10.1038/nature07239

  22. Ho, B. C., Andreasen, N. C., Nopolous, P., Arndt, S., Magnotta, V., & Flaum, M. (2003). Progressive structural brain abnormalities and their relationship to clinical outcome: A longitudinal magnetic resonance imaging study early in schizophrenia. Archives of General Psychiatry, 60(6), 585–594. doi:10.1001/archpsyc.60.6.585

  23.  van Ameslvoort, T., Daly, E., Henry, J., Roberson, D., Ng, V., Owen, M., Murphy, K. C., & Murphy, D. G. M. (2004). Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: Preliminary results of a structural magnetic resonance imaging study. Archives of General Psychiatry, 61(11), 1085–1096. doi:10.1001/archpsyc.61.11.1085

  24. Glausier, J. R., & Lewis, D. A. (2013). Dendritic spine pathology in schizophrenia. Neuroscience, 251, 90–107. doi:10.1016/j.neuroscience.2012.04.044

  25. Xiong, L. (2022). Analysis on the treatment of gray matter heterotopia epilepsy. Advances in Social Science, Education and Humanities Research, 858–863. doi:10.2991/assehr.k.220110.162

  26. Fry, A. E., Kerr, M. P., Gibbon, F., Turnpenny, P. D., Hamandi, K., Stoodley, N., Robertson, S. P., & Pilz, D. T. (2013). Neuropsychiatric disease in patients with periventricular heterotopia. The Journal of Neuropsychiatry and Clinical Neurosciences, 25(1), 26–31. doi:10.1176/appi.neuropsych.11110336

  27. Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: Overview and treatment options. Physical Therapy, 39(9), 638–645. PMID: 25210417

Dimple Kangriwala
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