Test-retest reliability of longitudinal task-based fMRI: Implications for developmental studies.

Great advances have been made in functional Magnetic Resonance Imaging (fMRI) studies, including the use of longitudinal design to more accurately identify changes in brain development across childhood and adolescence. While longitudinal fMRI studies are necessary for our understanding of typical and atypical patterns of brain development, the variability observed in fMRI blood-oxygen-level dependent (BOLD) signal and its test-retest reliability in developing populations remain a concern. Here we review the current state of test-retest reliability for child and adolescent fMRI studies (ages 5-18 years) as indexed by intraclass correlation coefficients (ICC). In addition to highlighting ways to improve fMRI test-retest reliability in developmental cognitive neuroscience research, we hope to open a platform for dialogue regarding longitudinal fMRI study designs, analyses, and reporting of results.

Default Mode Connectivity in Youth With Perinatally Acquired HIV.

Youth with perinatally acquired human immunodeficiency virus (PHIV+) survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. We evaluated whether markers of HIV disease severity relate to default mode resting-state functional connectivity in PHIV+ youth. We conducted resting-state functional neuroimaging and cognitive testing in a subset of 40 PHIV+ youth recruited from a single study site of the Adolescent Master Protocol study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Current and past HIV disease severity measures (nadir CD4 lymphocyte percentages and peak HIV RNA plasma levels) were obtained from medical charts. We evaluated associations of both HIV disease severity measures and cognitive functioning with between- and within- default mode network (DMN) connectivity using Analysis of Functional NeuroImaging multiple regression analyses, controlling for multiple comparisons. Of the 40 youth, 31 (mean age = 16.5 years) with minimal motion during scans were included. We observed global alterations in DMN within- and between-network connectivity, with significant associations between disease severity and DMN BOLD correlations. Furthermore, patterns of connectivity with the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) that varied as a function of peak HIV RNA were found to predict processing speed ability. Alterations in within- and between-network DMN connectivity in PHIV+ youth may reflect global reorganization of the DMN; this could lead to compensatory alterations in both the within- and between-connectivity of large-scale networks, which may ultimately relate to known cognitive processing difficulties in PHIV+ youth.

White matter microstructure among youth with perinatally acquired HIV is associated with disease severity.

OBJECTIVES: We investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally acquired HIV (PHIV). DESIGN: PHIV youth (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16 ±â€Š2 years) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter microstructure within PHIV youth. PHIV youth were compared with 314 controls from the Pediatric Imaging, Neurocognition and Genetics (PING) study. METHODS: Diffusion tensor imaging and tractography were utilized to assess white matter microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth. RESULTS: Whole brain fractional anisotropy was reduced, but radial and mean diffusivity were increased in PHIV compared with control youth. Within PHIV youth, more severe past HIV disease was associated with reduced fractional anisotropy of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated mean diffusivity of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO fractional anisotropy levels. CONCLUSION: Our findings suggest that PHIV youth have a higher risk of alterations in white matter microstructure than typically developing youth, and certain alterations are related to past disease severity. Further, white matter alterations potentially mediate associations between HIV disease and working memory.

Cortical gyrification and its relationships with cortical volume, cortical thickness, and cognitive performance in healthy mid-life adults.

Across species, greater cortical gyrification, or folding of the cortex, has been shown to be associated with higher cognitive abilities and is thought to reflect an evolutionary process aimed at maximizing the number of cerebral computational units while minimizing the energy and communication costs of larger brains. Relatively little is known about the significance of individual variation in gyrification in humans and how it relates to other aspects of cerebral structure and function. In the current study, we examined relationships between cortical gyrification and (i) cortical volume, (ii) cortical thickness, and (iii) executive functions. Participants were middle-aged healthy adults (44-48 years old, n=396) in a community-based sample. T1-weighted 3D structural magnetic resonance imaging scans were acquired in a Fast Field Echo sequence. Cortical gyrification, volume, and thickness were measured through the semi-automated software FreeSurfer. Results showed that cortical gyrification was strongly and positively related to cortical volume, but was negatively related to cortical thickness in many regions of the cortex. In addition, frontal gyrification was positively related to performance in working memory and mental flexibility tasks. These results support the view that greater cortical gyrification is related both to bigger brain volumes and better cognitive function, but not to greater cortical thickness. The results provide evidence of functional relevance of cortical gyrification development, and show that it can be a useful index to investigate structure-cognition relationships.

A longitudinal study: changes in cortical thickness and surface area during pubertal maturation.

Sex hormones have been shown to contribute to the organization and function of the brain during puberty and adolescence. Moreover, it has been suggested that distinct hormone changes in girls versus boys may contribute to the emergence of sex differences in internalizing and externalizing behavior during adolescence. In the current longitudinal study, the influence of within-subject changes in puberty (physical and hormonal) on cortical thickness and surface area was examined across a 2-year span, while controlling for age. Greater increases in Tanner Stage predicted less superior frontal thinning and decreases in precuneus surface area in both sexes. Significant Tanner Stage and sex interactions were also seen, with less right superior temporal thinning in girls but not boys, as well as greater decreases in the right bank of the superior temporal sulcus surface area in boys compared to girls. In addition, within-subject changes in testosterone over the 2-year follow-up period were found to relate to decreases in middle superior frontal surface area in boys, but increases in surface area in girls. Lastly, larger increases in estradiol in girls predicted greater middle temporal lobe thinning. These results show that within-subject physical and hormonal markers of puberty relate to region and sex-specific changes in cortical development across adolescence.

Executive function and cortical thickness in youths prenatally exposed to cocaine, alcohol and tobacco.

Small and detrimental, albeit inconsistent, effects of prenatal cocaine exposure (PCE) during early childhood have been reported. The teratogenic effects of prenatal alcohol (PAE) and tobacco exposure (PTE) on neurobehavior are more firmly established than PCE. We tested if co-exposure to all three drugs could be related to greater differences in brain structure than exposure to cocaine alone. Participants (n=42, PCE=27; age range=14-16 years) received an executive function battery prior to a T1-weighted 3T structural MRI scan. Cortical thickness was measured using FreeSurfer (v5.1). Fetal drug exposure was quantified through maternal self-reports usage during pregnancy. Using general linear modeling, we found no main effects of PCE on cortical thickness, but significant main effects of PAE and PTE in superior and medial frontal regions, after co-varying for the effects of age, sex, and each drug of exposure. Significant alcohol-by-tobacco interactions, and significant cocaine-by-alcohol interactions on cortical thickness in medial parietal and temporal regions were also observed. Poly-drug exposure and cognitive function also showed significant interactions with cortical thickness: lower cortical thickness was associated with better performance in PCE-exposed adolescents. Results suggest that although children with PCE have subtle but persistent brain cortical differences until mid-to-late adolescence.

Volume changes and brain-behavior relationships in white matter and subcortical gray matter in children with prenatal alcohol exposure.

Children with prenatal alcohol exposure (PAE) may have cognitive, behavioral and brain abnormalities. Here, we compare rates of white matter and subcortical gray matter volume change in PAE and control children, and examine relationships between annual volume change and arithmetic ability, behavior, and executive function. Participants (n = 75 PAE/64 control; age: 7.1-15.9 years) each received two structural magnetic resonance scans, ~2 years apart. Assessments included Wechsler Intelligence Scale for Children (WISC-IV), the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function. Subcortical white and gray volumes were extracted for each hemisphere. Group volume differences were tested using false discovery rate (q < 0.05). Analyses examined group-by-age interactions and group-score interactions for correlations between change in volume and raw behavioral scores. Results showed that subjects with PAE had smaller volumes than control subjects across the brain. Significant group-score interactions were found in temporal and parietal regions for WISC arithmetic scores and in frontal and parietal regions for behavioral measures. Poorer cognitive/ behavioral outcomes were associated with larger volume increases in PAE, while control subjects generally showed no significant correlations. In contrast with previous results demonstrating different trajectories of cortical volume change in PAE, our results show similar rates of subcortical volume growth in subjects with PAE and control subjects. We also demonstrate abnormal brain-behavior relationships in subjects with PAE, suggesting different use of brain resources. Our results are encouraging in that, due to the stable volume differences, there may be an extended window of opportunity for intervention in children with PAE.

The role of testosterone and estradiol in brain volume changes across adolescence: a longitudinal structural MRI study.

It has been postulated that pubertal hormones may drive some neuroanatomical changes during adolescence, and may do so differently in girls and boys. Here, we use growth curve modeling to directly assess how sex hormones [testosterone (T) and estradiol (E2)] relate to changes in subcortical brain volumes utilizing a longitudinal design. 126 adolescents (63 girls), ages 10 to 14, were imaged and restudied ∼2 years later. We show, for the first time, that best-fit growth models are distinctly different when using hormones as compared to a physical proxy of pubertal maturation (Tanner Stage) or age, to predict brain development. Like Tanner Stage, T and E2 predicted white matter and right amygdala growth across adolescence in both sexes, independent of age. Tanner Stage also explained decreases in both gray matter and caudate volumes, whereas E2 explained only gray matter decreases and T explained only caudate volume decreases. No pubertal measures were related to hippocampus development. Although specificity was seen, sex hormones had strikingly similar relationships with white matter, gray matter, right amygdala, and bilateral caudate volumes, with larger changes in brain volume seen at early pubertal maturation (as indexed by lower hormone levels), followed by less robust, or even reversals in growth, by late puberty. These novel longitudinal findings on the relationship between hormones and brain volume change represent crucial first steps toward understanding which aspects of puberty influence neurodevelopment.

Sex differences in cortical thickness in middle aged and early old-aged adults: Personality and Total Health Through Life study.

INTRODUCTION: The study investigated sex differences in cortical thickness in middle-aged (MA, 44-48 years old, n = 397) and early old-aged (OA, 64-68 years old, n = 398) adults in a community-based sample. METHODS: T1-weighted three-dimensional structural magnetic resonance imaging scans were acquired in a Fast Field Echo sequence, and cortical thickness was measured with a surface-based segmentation procedure ( http://surfer.nmr.mgh.harvard.edu ). RESULTS: Results showed that after correcting for age, MA males had predominantly thicker superior temporal cortices, while MA females had thicker occipital, posterior cingulate, precentral, and postcentral cortices. Sex differences in OA adults were less prominent than those in MA adults with females showing thicker temporal and posterior cingulate cortices and males showing thicker rostral middle frontal regions. Between-cohort comparisons revealed that when compared with MA males, OA males showed many regions with significantly thinner cortices, but this pattern was less pronounced for OA females. Our results suggest that sex differences in cortical thickness are age specific, as larger differences in cortical thickness were found in MA compared to OA adults. CONCLUSION: The results of the present study indicate that the inconsistencies in sexual dimorphism that have been reported in the literature are partly due to the variable and transitory nature of cortical thickness differences with age.

APOE genotype and entorhinal cortex volume in non-demented community-dwelling adults in midlife and early old age.

The apolipoprotein E (APOE) ε4 allele is a risk factor for the neuropathological decline accompanying Alzheimer's disease (AD) while, conversely, the ε2 allele offers protection. One of the brain structures exhibiting the earliest changes associated with the disease is the entorhinal cortex. We therefore investigated the volumes of the entorhinal cortex and other structures in the medial temporal lobe including the parahippocampal gyrus, temporal pole, and inferior, middle, and superior temporal cortices, in relation to APOE genotype. Our main objectives were to determine if (a) volumes systematically varied according to allele in a stepwise fashion, ε2 > ε3 > ε4, and (b) associations varied according to age. We investigate this association in 627 non-demented community-dwelling adults in middle age (44 to 48 years; n = 314) and older age (64 to 68 years; n = 313) who underwent structural MRI scans. We found no evidence of APOE-related variation in brain volumes in the age groups examined. We conclude that if a ε2 > ε3 > ε4 pattern in brain volumes does emerge in non-demented adults living in the community in old age, it is not until after the age of 68 years.

Relationships between cognitive function and frontal grey matter volumes and thickness in middle aged and early old-aged adults: the PATH Through Life Study.

The study examined the relationship of lateral frontal cortical volume and thickness with cognitive function in two samples of healthy middle aged (MA, 44-48 years old) and early old-age (OA, 64-68 years old) adults. T1-weighted magnetic resonance imaging scans were acquired in 400 MA and 397 OA adults from respective random community samples. Cortical volumes and thickness were measured with a surface-based segmentation procedure (http://surfer.nmr.mgh.harvard.edu). Volumes of lateral frontal grey matter were found to be significantly lower for OA than MA. Structure-function relationships were investigated using path analyses. In OA, smaller lateral frontal volumes were associated with better episodic memory (EM) (p<0.012, B=-0.117), and Symbol-Digit Modalities Test (SDM) (p<0.031, B=-0.118) performance. Smaller frontal cortical thickness was also associated with better EM (p<0.01) and SDM (p<0.01) performance in OA. However, in MA greater cortical thickness was associated with better EM and (p<0.01) and reaction time (RT) (p<0.01). OA cohort showed significant positive correlations between Total Brain Volume and SDM, Digit-Backwards span and RT. Possible explanations and implications of the relationships in the context of cognitive aging in healthy adults, and limitations of cross-sectional research are discussed.