Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.

Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals’ genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum’s role in autism.

Background. Exercise promotes repair processes in the mouse brain and improves cognition in both mice and humans. It is not known whether these benefits translate to human brain injury, particularly the significant injury observed in children treated for brain tumors. Methods. We conducted a clinical trial with crossover of exercise training versus no training in a restricted sample of children treated with radiation for brain tumors. The primary outcome was change in brain structure using MRI measures of white matter (ie, fractional anisotropy [FA]) and hippocampal volume [mm 3 ]). The secondary outcome was change in reaction time (RT)/accuracy across tests of attention, processing speed, and short-term memory. Linear mixed modeling was used to test the effects of time, training, training setting, and carryover. Results. Twenty-eight participants completed training in either a group (n=16) or a combined group/home (n=12) setting. Training resulted in increased white matter FA (Δ=0.05, P<.001). A carryover effect was observed for participants ~12 weeks after training (Δ=0.05, P<.001). Training effects were observed for hippocampal volume (Δ=130.98mm 3 ; P=.001) and mean RT (Δ=-457.04ms, P=0.36) but only in the group setting. Related carryover effects for hippocampal volume (Δ=222.81mm 3 , P=.001), and RT (Δ=-814.90ms, P=.005) were also observed. Decreased RT was predicted by increased FA (R=-0.62, P=.01). There were no changes in accuracy. Conclusions. Exercise training is an effective means for promoting white matter and hippocampal recovery and improving reaction time in children treated with cranial radiation for brain tumors. Key wordsbrain recovery | cranial radiation | exercise | neuroplasticity | pediatric brain tumor