Sex differences in pediatric traumatic brain injury

Abstract

The response of the developing brain to traumatic injury is different from the response of the mature, adult brain. There are critical developmental trajectories in the young brain, whereby injury can lead to long term functional abnormalities. Emerging preclinical and clinical literature supports the presence of significant sex differences in both the response to and the recovery from pediatric traumatic brain injury (TBI). These sex differences are seen at all pediatric ages, including neonates/infants, pre-pubertal children, and adolescents. As importantly, the response to neuroprotective therapies or treatments can differ between male and females subjects. These sex differences can result from several biologic origins, and may manifest differently during the various phases of brain and body development. Recognizing and understanding these potential sex differences is crucial, and should be considered in both preclinical and clinical studies of pediatric TBI.

Keywords: Cerebral metabolism; Excitotoxicity; Gender; Mitochondria; Neuroinflammation; Sex.

Figure 1:. There are multiple types of sex differences in the brain.

The most frequent conceptualizations of sex differences in the brain involve different endpoints in males and females. a,b) These may be of different forms, and hence referred to as a) sexually dimorphic (red and blue lines representing each sex differ in form), or they may be a difference in average response along a continuum, and thus a b) sex difference (green line represents a continuum of possible endpoints, and sexes represented by dashed lines differ in their average value on this continuum). b,c) In some instances males and females are at the same point but in response to a challenge, such as stress, or over the course of the lifetime, they may diverge to different places, either along the same continuum (b) or taking on different forms all together (c). d) Alternatively, there are instances where males and females appear to be the same but there are underlying or latent sex differences. For instance, neural responses (represented by green circle) may appear similar in males and females but the cellular and/or molecular mechanisms by which they are achieved may be quite distinct (blue and red arrows represent unique pathways to the same endpoint). e) Or, one sex may be constrained by physiology inherent to reproduction, but evolved new ways of achieving the same endpoint, such as unique neural circuits to promote parenting behavior in males, referred to as convergence (each sex, represented by the square and triangle, converge on the same endpoint represented by the green circle). f) Lastly, a disease or other endpoint may be highly similar (circle) in the two sexes but occur at varying frequency (size of circle).

Figure 2:. Critical and sensitive periods in the establishment of sex differences in the brain.

In rodents there is a critical period in males that begins in utero with the onset of testicular androgen production which initiates the process of masculinization of the brain. Females, however, remain sensitive to the impact of exogenous hormone treatment into the first postnatal week and can be essentially sex reversed if exposed during that time. Thus, the timing of the critical period in males and sensitive period in females are overlapping but not identical. In humans convergent evidence indicates there is a critical period for masculinization that begins and ends in utero but we remain unclear about the potential for a postnatal sensitive period in females as well as the functional significance of the “mini-puberty” that occurs in the first few months of life.

Figure 3.. Innate sex differences in the developing brain can tip the balance in pathobiology of pediatric TBI.

Key differences in mechanisms of neurodevelopment may put males closer to a pathobiologic threshold. During early life, males show a greater propensity toward inflammatory pathways, sensitivity to excitotoxicity, reduced mitochondrial glutathione content and a prolonged period of excitatory GABAa activity. These differences may explain observed increases in Iba1 expression, reduced mitochondrial respiration, and impaired CBF autoregulation seen in response to pediatric TBI. However, for many known pathobiologic pathways active in the pediatric TBI response, sex has not been examined as a factor.