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Literal holes in the brain tissue can be caused by genetic flaws, injury, metabolic disorders, and some rare diseases (such as variant Creutzfeldt-Jakob disease). These are rare conditions and it is possible for individuals to survive despite losing a significant part of the physical brain.

Holes in the "mind" (brain function or memory) can likewise be caused by injury, or by psychological trauma, or by some drugs that affect the brain chemistry.

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