To the Editor: Lynn D. Selemon, Ph.D., and colleagues (1) suggested that frontal cortical volume is reduced in schizophrenia. We suggest the possibility that a subtle fixation artifact may offer an alternative and more comprehensive explanation for their results.

Past dogma erroneously suggested that the aging process of normal adulthood is associated with a reduction in cortical neuron number. This conclusion was based on data showing that neuronal density in young adults was higher than in middle-aged to older individuals. The apparent age-related reductions in cortical neuronal density were later shown to be caused by an age-related tissue fixation shrinkage artifact that caused cortices from younger individuals to shrink more than older ones. Unbiased stereological assessments have demonstrated that there is minimal if any neuronal cell loss or cortical thickness decrements before the age of 55 (reviewed in references 2–4).

The excess fixation-related cortical shrinkage of younger brains is likely because of their lower levels of intracortical myelin. Intracortical myelination increases during adulthood to peak in the mid to late fifth decade of life in association with regions such as the frontal and temporal lobes (reviewed in references 3 and 4), and the lipid-rich myelin reduces the amount of dehydration-related cortical shrinkage (5, 6). Thus, the lower the myelin content of any cortex, the more fixation shrinkage is expected.

Genetic, imaging, and cellular evidence for a myelination defect in schizophrenia has been published (reviewed in references 3, 4, and 7). A 22% reduction in frontal lobe cortical oligodendrocyte density has been observed (7). This reduction may itself be an underestimate for the same reasons (excessive shrinkage upon fixation), as discussed.

Therefore, it is possible that the apparent reduction in cortical volume in the frontal lobes of schizophrenics and the associated evidence of "reduced neuropil" in schizophrenia (1) may in large part be due to a myelination deficit of this and other regions that normally continue to myelinate in adulthood (2–4). We suggest that oligodendrocyte and myelin sheath reductions result in a modest loss of cortical neuropil and that this loss is likely further amplified by fixation artifact (5, 6).

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