Gender differences in cell volume fraction (CVF): a structural parameter reflecting the energy efficiency of maintaining the resting membrane potential

The cell volume fraction (CVF) of the human brain is high (similar to 82%) and is preserved across healthy aging while the brain declines in volume. These two observations, supported by several independent techniques, suggest that CVF is an important structural parameter. A new biophysical model is presented that incorporates CVF into the Goldman equation of classical membrane electrophysiology. The Goldman equation contains few structural constraints beyond two compartments separated by a semipermeable membrane supporting ion gradients. As potassium is the most permeable ion in the resting state, the resting membrane potential is determined by the potassium ion gradient. This biophysical model indicates that the sodium-potassium ion pumps use less energy at high CVF to maintain the resting membrane potential, explaining the high value of CVF and its conservation with healthy aging. CVF is measured to be statistically significantly higher in the brains of males compared with females, suggesting a structural requirement for higher energy efficiency in the larger male brain to support the greater number of neurons and synapses. As CVF can be measured in humans using quantitative sodium MRI and has potential implications for brain health, CVF may be a quantitative parameter that is useful for assessment of brain health, especially in patients with diseases such as dementia and psychiatric disease that do not have anatomical correlates detectable by clinical proton MRI.