Multiple studies over several decades have provided evidence that both electrolytes and organic osmolytes play crucial roles in regulating brain volume, both during increases as well as during decreases in extracellular fluid osmolality. In both situations, however, changes in brain electrolyte contents appear to occur more rapidly, and represent the first line of defense of brain volume during acute perturbations of body fluid tonicity, while organic osmolytes allow adaptation to more chronic perturbations. For both hyperosmolality and hypoosmolality, the rate of development of the disorder is an important determinant of neurological morbidity and mortality, since sufficiently rapid changes in tonicity can exceed the brain's capacity to regulate its volume leading to more severe degrees of brain edema or dehydration.

Recovery from both hyper- and hypoosmolality requires reversal of the adaptive processes that enabled regulation of brain volume in response to the initial insult. However, adaptation and recovery are not symmetrical processes. Marked differences occur in the speed with which the brain is able to lose or to reaccumulate different types of solutes after recovery from chronic disturbances of body fluid tonicity. In general, accumulation, or reaccumulation, of organic solutes by brain tissue is a much slower process than volume regulatory losses of such solutes. As with the adaptation process, the rate of recovery is an important determinant of subsequent morbidity and mortality, since rapid corrections of osmolality can also exceed the capacity of the brain to readjust its solute content, and consequently its volume, back to normal levels.

Whether or not transient excesses or deficiencies of either electrolytes or specific organic osmolytes in brain intracellular or extracellular fluid contribute to functional disturbances independently of changes in brain volume is an intriguing question that has not been sufficiently evaluated. Also remaining to be answered are questions regarding other physiological, pathophysiological, and pharmacological factors that either impair or enhance volume regulatory processes, and thereby modify the neurological manifestations accompanying disorders of body fluid osmolality in humans. Finally, a complete understanding of the cellular mechanisms underlying adaptation to and deadaptation from acute and chronic perturbations of body osmolality will be essential to design the most enlightened, and therefore appropriate, treatments for these disorders.

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