The ABCD stop signal data: Response to Bissett et al.

This paper responds to a recent critique by Bissett et al. of the fMRI Stop task used in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®). The critique focuses primarily on a task design feature related to race model assumptions (i.e., that the Go and Stop processes are fully independent). In response, we note that the race model is quite robust against violations of its assumptions. Most importantly, while Bissett raises conceptual concerns with the task we focus here on analyzes of the task data and conclude that the concerns appear to have minimal impact on the neuroimaging data (the validity of which do not rely on race model assumptions) and have far less of an impact on the performance data than the critique suggests. We note that Bissett did not apply any performance-based exclusions to the data they analyzed, a number of the trial coding errors they flagged were already identified and corrected in ABCD annual data releases, a number of their secondary concerns reflect sensible design decisions and, indeed, their own computational modeling of the ABCD Stop task suggests the problems they identify have just a modest impact on the rank ordering of individual differences in subject performance.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Polygenic risk for psychiatric disorders correlates with executive function in typical development.

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome-wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.

Genome-wide association study of shared components of reading disability and language impairment.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

Recovery of white matter tracts in regions of peritumoral FLAIR hyperintensity with use of restriction spectrum imaging.

BACKGROUND AND PURPOSE: DTI is being increasingly used to visualize critical white matter tracts adjacent to brain tumors before neurosurgical resection. However, brain tumors, particularly high-grade gliomas, are typically surrounded by regions of FLAIR hyperintensity that include edema, which increase isotropic diffusion, degrading the ability of standard DTI to uncover orientation estimates within these regions. We introduce a new technique, RSI, which overcomes this limitation by removing the spherical, fast diffusion component introduced by edema, providing better analysis of white matter architecture. MATERIALS AND METHODS: A total of 10 patients with high-grade gliomas surrounded by FLAIR-HI that at least partially resolved on follow-up imaging were included. All patients underwent RSI and DTI at baseline (FLAIR-HI present) and at follow-up (FLAIR-HI partially resolved). FA values obtained with RSI and DTI were compared within regions of FLAIR-HI and NAWM at both time points. RESULTS: RSI showed higher FA in regions of FLAIR-HI and NAWM relative to DTI, reflecting the ability of RSI to specifically measure the slow, restricted volume fraction in regions of edema and NAWM. Furthermore, a method by time interaction revealed that FA estimates increased when the FLAIR-HI resolved by use of standard DTI but remained stable with RSI. Tractography performed within the region of FLAIR-HI revealed the superior ability of RSI to track fibers through severe edema relative to standard DTI. CONCLUSIONS: RSI improves the quantification and visualization of white matter tracts in regions of peritumoral FLAIR-HI associated with edema relative to standard DTI and may provide a valuable tool for neurosurgical planning.

CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer's disease risk in an APOE-dependent manner.

Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer's disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.

Role of frontotemporal fiber tract integrity in task-switching performance of healthy controls and patients with temporal lobe epilepsy.

The objective of this study is to investigate the relationships among frontotemporal fiber tract compromise and task-switching performance in healthy controls and patients with temporal lobe epilepsy (TLE). We performed diffusion tensor imaging (DTI) on 30 controls and 32 patients with TLE (15 left TLE). Fractional anisotropy (FA) was calculated for four fiber tracts [uncinate fasciculus (UncF), arcuate fasciculus (ArcF), dorsal cingulum (CING), and inferior fronto-occipital fasciculus (IFOF)]. Participants completed the Trail Making Test-B (TMT-B) and Verbal Fluency Category Switching (VFCS) test. Multivariate analyses of variances (MANOVAs) were performed to investigate group differences in fiber FA and set-shifting performances. Canonical correlations were used to examine the overall patterns of structural-cognitive relationships and were followed by within-group bivariate correlations. We found a significant canonical correlation between fiber FA and task-switching performance. In controls, TMT-B correlated with left IFOF, whereas VFCS correlated with FA of left ArcF and left UncF. These correlations were not significant in patients with TLE. We report significant correlations between frontotemporal fiber tract integrity and set-shifting performance in healthy controls that appear to be absent or attenuated in patients with TLE. These findings suggest a breakdown of typical structure-function relationships in TLE that may reflect aberrant developmental or degenerative processes.

Global clinical dementia rating of 0.5 in MCI masks variability related to level of function.

OBJECTIVE: To evaluate whether ratings on Clinical Dementia Rating (CDR) items related to instrumental activities of daily living (IADL) are associated with cognitive or brain morphometric characteristics of participants with mild cognitive impairment (MCI) and global CDR scores of 0.5. METHODS: Baseline cognitive and morphometric data were analyzed for 283 individuals with MCI who were divided into 2 groups (impaired and intact) based on their scores on the 3 CDR categories assessing IADL. Rates of progression to Alzheimer disease (AD) over 2 years were also compared in the 2 groups. RESULTS: The impaired IADL MCI group showed a more widespread pattern of gray matter loss involving frontal and parietal regions, worse episodic memory and executive functions, and a higher percentage of individuals progressing to AD than the relatively intact IADL MCI group. CONCLUSIONS: The results demonstrate the importance of considering functional information captured by the CDR when evaluating individuals with MCI, even though it is not given equal weight in the assignment of the global CDR score. Worse impairment on IADL items was associated with greater involvement of brain regions beyond the mesial temporal lobe. The conventional practice of relying on the global CDR score as currently computed underutilizes valuable IADL information available in the scale, and may delay identification of an important subset of individuals with MCI who are at higher risk of clinical decline.

Changes in fiber tract integrity and visual fields after anterior temporal lobectomy.

OBJECTIVE: To investigate postoperative changes in fiber tract integrity in patients with temporal lobe epilepsy (TLE) following anterior temporal lobectomy (ATL) and to determine whether postoperative changes are 1) stable vs progressive and 2) related to visual field defects. METHODS: Diffusion tensor imaging (DTI) was obtained in 7 patients with TLE before, 2 months after, and 1 year after ATL. Changes in fractional anisotropy (FA) were evaluated in a whole-brain voxel-wise analysis, as well within specific fiber tracts. Repeated-measures analysis of variance was performed to examine the time course of FA changes within ipsilateral and contralateral fiber tracts. Quantitative visual field analysis was performed to determine whether decreases in regional FA were related to the extent or location of visual field defects. RESULTS: Patients showed decreased FA 2 months post-ATL in ipsilateral fiber tracts transected during surgery (parahippocampal cingulum, uncinate fasciculus, inferior longitudinal fasciculus, and fornix), as well as in fiber tracts not directly transected (inferior fronto-occipital fasciculus and corpus callosum). Additional decreases in FA were not observed from 2 months to 1 year post-ATL. Visual field defects in most patients were characterized by incomplete quadrantanopsias. However, FA reductions in one patient extended into temporo-occipital cortex and the splenium of the corpus callosum and were associated with a complete hemianopia. CONCLUSIONS: Wallerian degeneration is apparent 2 months following unilateral ATLs in ipsilateral fibers directly and indirectly affected during surgery. These changes do not appear to progress over the course of a year, but may correlate with the nature and extent of postoperative visual field defects.

Six-month atrophy in MTL structures is associated with subsequent memory decline in elderly controls.

Neurodegeneration precedes the onset of dementias such as Alzheimer's by several years. Recent advances in volumetric imaging allow quantification of subtle neuroanatomical change over time periods as short as six months. This study investigates whether neuroanatomical change in medial temporal lobe subregions is associated with later memory decline in elderly controls. Using high-resolution, T1-weighted magnetic resonance images acquired at baseline and six-month follow-up, change in cortical thickness and subcortical volumes was measured in 142 healthy elderly subjects (aged 59-90 years) from the ADNI cohort. Regression analysis was used to identify whether change in fourteen subregions, selected a priori, was associated with declining performance on memory tests from baseline to two-year follow-up. Percent thickness change in the right fusiform and inferior temporal cortices and expansion of the right inferior lateral ventricle were found to be significant predictors of subsequent decline on memory-specific neuropsychological measures. These results demonstrate that six-month regional neurodegeneration can be quantified in the healthy elderly and might help identify those at risk for subsequent cognitive decline.