Pediatric Brain Development in Down Syndrome: A Field in Its Infancy

Abstract

Objectives: As surprisingly little is known about the developing brain studied in vivo in youth with Down syndrome (DS), the current review summarizes the small DS pediatric structural neuroimaging literature and begins to contextualize existing research within a developmental framework.

Methods: A systematic review of the literature was completed, effect sizes from published studies were reviewed, and results are presented with respect to the DS cognitive behavioral phenotype and typical brain development.

Results: The majority of DS structural neuroimaging studies describe gross differences in brain morphometry and do not use advanced neuroimaging methods to provide nuanced descriptions of the brain. There is evidence for smaller total brain volume (TBV), total gray matter (GM) and white matter, cortical lobar, hippocampal, and cerebellar volumes. When reductions in TBV are accounted for, specific reductions are noted in subregions of the frontal lobe, temporal lobe, cerebellum, and hippocampus. A review of cortical lobar effect sizes reveals mostly large effect sizes from early childhood through adolescence. However, deviance is smaller in adolescence. Despite these smaller effects, frontal GM continues to be largely deviant in adolescence. An examination of age-frontal GM relations using effect sizes from published studies and data from Lee et al. (2016) reveals that while there is a strong inverse relationship between age and frontal GM volume in controls across childhood and adolescence, this is not observed in DS.

Conclusions: Further developmentally focused research, ideally using longitudinal neuroimaging, is needed to elucidate the nature of the DS neuroanatomic phenotype during childhood and adolescence. (JINS, 2018, 24, 966-976).

Trial registration: ClinicalTrials.gov NCT00001246.

Keywords: Cerebellum; Cerebral cortex; Frontal lobe; Hippocampus; Magnetic resonance imaging; Trisomy 21.

Figures

Figure 1

Effect size estimates (Cohen’s d) of DS-Control group differences for lobar volumes (total, GM, and WM) from published research studies reporting raw findings plotted as a function of age. N.B., negative effect size estimates indicate smaller volume in DS group. Line represents average volume effect size with upper and lower limits.

Figure 2

Gray matter volume for each lobe plotted by age and effect size. N.B., negative effect sizes denotes smaller volume in the DS group.

Figure 3

Frontal GM – Age relations in DS relative to typically developing (TD) controls. Panel A shows a hypothetical DS frontal GM curve (gray line) created from effect size estimates from three published studies of youth with DS with mean ages of 5, 9, and 15 (Carter, Capone, & Kaufmann, 2008; Kates, Folley, Lanham, Capone, & Kaufmann, 2002; Lee et al., 2016). These effect size estimates were used as a measure of degree of deviance from typical development by “working backwards” from Cohen’s d (e.g., for the study with mean age of 5: DShypothetical volume age 5 = Mvol TD age 5 – (Cohen’s dDS age 5 * SDTD age 5). In order to plot these relative to frontal GM volume across childhood for TD peers, frontal GM data from the NIH Normative Brain Development Study were used as a comparison group. Effect sizes from the three DS studies were used to approximate standard deviations of difference between youth with DS and TD youth of a similar age (based on the mean age of the DS group in the published study). These three points are plotted as a function of the mean age of the DS group in the respective study. In addition, data are plotted for frontal GM as a function of age for TD youth (black) ages 5 to 15 from the NIH sample. Panel B shows frontal GM – age relations examined cross-sectionally for DS and TD control groups from Lee et al. (2016). The data plotted here are from a subsample of the participants, ages 5-15, from the DS (gray) and TD (black) groups.