ASLPrep: a platform for processing of arterial spin labeled MRI and quantification of regional brain perfusion.

Arterial spin labeled (ASL) magnetic resonance imaging (MRI) is the primary method for noninvasively measuring regional brain perfusion in humans. We introduce ASLPrep, a suite of software pipelines that ensure the reproducible and generalizable processing of ASL MRI data.

Sex differences in the functional topography of association networks in youth.

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here, we leveraged an advanced machine learning method (sparsity-regularized non-negative matrix factorization) to define individualized functional networks in 693 youth (ages 8 to 23 y) who underwent functional MRI as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 82.9% accuracy (P < 0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention, default mode, and frontoparietal networks. Mass univariate analyses using generalized additive models with penalized splines provided convergent results. Furthermore, transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography were spatially correlated with the expression of genes on the X chromosome. These results highlight the role of sex as a biological variable in shaping functional topography.

Diffusion MRI head motion correction methods are highly accurate but impacted by denoising and sampling scheme.

Head motion correction is particularly challenging in diffusion-weighted MRI (dMRI) scans due to the dramatic changes in image contrast at different gradient strengths and directions. Head motion correction is typically performed using a Gaussian Process model implemented in FSL's Eddy. Recently, the 3dSHORE-based SHORELine method was introduced that does not require shell-based acquisitions, but it has not been previously benchmarked. Here we perform a comprehensive evaluation of both methods on realistic simulations of a software fiber phantom that provides known ground-truth head motion. We demonstrate that both methods perform remarkably well, but that performance can be impacted by sampling scheme and the extent of head motion and the denoising strategy applied before head motion correction. Furthermore, we find Eddy benefits from denoising the data first with MP-PCA. In sum, we provide the most extensive known benchmarking of dMRI head motion correction, together with extensive simulation data and a reproducible workflow. PRACTITIONER POINTS: Both Eddy and SHORELine head motion correction methods performed quite well on a large variety of simulated data. Denoising with MP-PCA can improve head motion correction performance when Eddy is used. SHORELine effectively corrects motion in non-shelled diffusion spectrum imaging data.

A practical evaluation of measures derived from compressed sensing diffusion spectrum imaging.

Diffusion Spectrum Imaging (DSI) using dense Cartesian sampling of q-space has been shown to provide important advantages for modeling complex white matter architecture. However, its adoption has been limited by the lengthy acquisition time required. Sparser sampling of q-space combined with compressed sensing (CS) reconstruction techniques has been proposed as a way to reduce the scan time of DSI acquisitions. However prior studies have mainly evaluated CS-DSI in post-mortem or non-human data. At present, the capacity for CS-DSI to provide accurate and reliable measures of white matter anatomy and microstructure in the living human brain remains unclear. We evaluated the accuracy and inter-scan reliability of 6 different CS-DSI schemes that provided up to 80% reductions in scan time compared to a full DSI scheme. We capitalized on a dataset of 26 participants who were scanned over eight independent sessions using a full DSI scheme. From this full DSI scheme, we subsampled images to create a range of CS-DSI images. This allowed us to compare the accuracy and inter-scan reliability of derived measures of white matter structure (bundle segmentation, voxel-wise scalar maps) produced by the CS-DSI and the full DSI schemes. We found that CS-DSI estimates of both bundle segmentations and voxel-wise scalars were nearly as accurate and reliable as those generated by the full DSI scheme. Moreover, we found that the accuracy and reliability of CS-DSI was higher in white matter bundles that were more reliably segmented by the full DSI scheme. As a final step, we replicated the accuracy of CS-DSI in a prospectively acquired dataset (n = 20, scanned once). Together, these results illustrate the utility of CS-DSI for reliably delineating in vivo white matter architecture in a fraction of the scan time, underscoring its promise for both clinical and research applications.

Network enrichment significance testing in brain-phenotype association studies.

Functional networks often guide our interpretation of spatial maps of brain-phenotype associations. However, methods for assessing enrichment of associations within networks of interest have varied in terms of both scientific rigor and underlying assumptions. While some approaches have relied on subjective interpretations, others have made unrealistic assumptions about spatial properties of imaging data, leading to inflated false positive rates. We seek to address this gap in existing methodology by borrowing insight from a method widely used in genetics research for testing enrichment of associations between a set of genes and a phenotype of interest. We propose network enrichment significance testing (NEST), a flexible framework for testing the specificity of brain-phenotype associations to functional networks or other sub-regions of the brain. We apply NEST to study enrichment of associations with structural and functional brain imaging data from a large-scale neurodevelopmental cohort study.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

QSIPrep: an integrative platform for preprocessing and reconstructing diffusion MRI data.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

Predicting patients with dementia most at risk of needing psychiatric in-patient or enhanced community care using routinely collected clinical data: retrospective multi-site cohort study.

BACKGROUND: Dementia is a common and progressive condition whose prevalence is growing worldwide. It is challenging for healthcare systems to provide continuity in clinical services for all patients from diagnosis to death. AIMS: To test whether individuals who are most likely to need enhanced care later in the disease course can be identified at the point of diagnosis, thus allowing the targeted intervention. METHOD: We used clinical information collected routinely in de-identified electronic patient records from two UK National Health Service (NHS) trusts to identify at diagnosis which individuals were at increased risk of needing enhanced care (psychiatric in-patient or intensive (crisis) community care). RESULTS: We examined the records of a total of 25 326 patients with dementia. A minority (16% in the Cambridgeshire trust and 2.4% in the London trust) needed enhanced care. Patients who needed enhanced care differed from those who did not in age, cognitive test scores and Health of the Nation Outcome Scale scores. Logistic regression discriminated risk, with an area under the receiver operating characteristic curve (AUROC) of up to 0.78 after 1 year and 0.74 after 4 years. We were able to confirm the validity of the approach in two trusts that differed widely in the populations they serve. CONCLUSIONS: It is possible to identify, at the time of diagnosis of dementia, individuals most likely to need enhanced care later in the disease course. This permits the development of targeted clinical interventions for this high-risk group.

Associations between neighborhood socioeconomic status, parental education, and executive system activation in youth.

Socioeconomic status (SES) can impact cognitive performance, including working memory (WM). As executive systems that support WM undergo functional neurodevelopment during adolescence, environmental stressors at both individual and community levels may influence cognitive outcomes. Here, we sought to examine how SES at the neighborhood and family level impacts task-related activation of the executive system during adolescence and determine whether this effect mediates the relationship between SES and WM performance. To address these questions, we studied 1,150 youths (age 8-23) that completed a fractal n-back WM task during functional magnetic resonance imaging at 3T as part of the Philadelphia Neurodevelopmental Cohort. We found that both higher neighborhood SES and parental education were associated with greater activation of the executive system to WM load, including the bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and precuneus. The association of neighborhood SES remained significant when controlling for task performance, or related factors like exposure to traumatic events. Furthermore, high-dimensional multivariate mediation analysis identified distinct patterns of brain activity within the executive system that significantly mediated the relationship between measures of SES and task performance. These findings underscore the importance of multilevel environmental factors in shaping executive system function and WM in youth.

ModelArray: An R package for statistical analysis of fixel-wise data.

Diffusion MRI is the dominant non-invasive imaging method used to characterize white matter organization in health and disease. Increasingly, fiber-specific properties within a voxel are analyzed using fixels. While tools for conducting statistical analyses of fixel-wise data exist, currently available tools support only a limited number of statistical models. Here we introduce ModelArray, an R package for mass-univariate statistical analysis of fixel-wise data. At present, ModelArray supports linear models as well as generalized additive models (GAMs), which are particularly useful for studying nonlinear effects in lifespan data. In addition, ModelArray also aims for scalable analysis. With only several lines of code, even large fixel-wise datasets can be analyzed using a standard personal computer. Detailed memory profiling revealed that ModelArray required only limited memory even for large datasets. As an example, we applied ModelArray to fixel-wise data derived from diffusion images acquired as part of the Philadelphia Neurodevelopmental Cohort (n = 938). ModelArray revealed anticipated nonlinear developmental effects in white matter. Moving forward, ModelArray is supported by an open-source software development model that can incorporate additional statistical models and other imaging data types. Taken together, ModelArray provides a flexible and efficient platform for statistical analysis of fixel-wise data.

Brain Growth Charts for Quantitative Analysis of Pediatric Clinical Brain MRI Scans with Limited Imaging Pathology.

Background Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. These barriers have curtailed retrospective studies of clinical brain MRI scans compared with more costly prospectively acquired research-quality brain MRI scans. Purpose To provide a benchmark for neuroanatomic variability in clinically acquired brain MRI scans with limited imaging pathology (SLIPs) and to evaluate if growth charts from curated clinical MRI scans differed from research-quality MRI scans or were influenced by clinical indication for the scan. Materials and Methods In this secondary analysis of preexisting data, clinical brain MRI SLIPs from an urban pediatric health care system (individuals aged ≤22 years) were scanned across nine 3.0-T MRI scanners. The curation process included manual review of signed radiology reports and automated and manual quality review of images without gross pathology. Global and regional volumetric imaging phenotypes were measured using two image segmentation pipelines, and clinical brain growth charts were quantitatively compared with charts derived from a large set of research controls in the same age range by means of Pearson correlation and age at peak volume. Results The curated clinical data set included 532 patients (277 male; median age, 10 years [IQR, 5-14 years]; age range, 28 days after birth to 22 years) scanned between 2005 and 2020. Clinical brain growth charts were highly correlated with growth charts derived from research data sets (22 studies, 8346 individuals [4947 male]; age range, 152 days after birth to 22 years) in terms of normative developmental trajectories predicted by the models (median r = 0.979). Conclusion The clinical indication of the scans did not significantly bias the output of clinical brain charts. Brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement research data sets. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ertl-Wagner and Pai in this issue.

Psychosis spectrum features, neurocognition and functioning in a longitudinal study of youth with 22q11.2 deletion syndrome.

BACKGROUND: Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome. METHODS: 157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS-). RESULTS: We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS- group. Neurocognitive performance was generally comparable in PS+ and PS- groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS- counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change. CONCLUSIONS: Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

Altered functional brain dynamics in chromosome 22q11.2 deletion syndrome during facial affect processing.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder associated with multiple congenital anomalies, variable medical features, and neurodevelopmental differences resulting in diverse psychiatric phenotypes, including marked deficits in facial memory and social cognition. Neuroimaging in individuals with 22q11.2DS has revealed differences relative to matched controls in BOLD fMRI activation during facial affect processing tasks. However, time-varying interactions between brain areas during facial affect processing have not yet been studied with BOLD fMRI in 22q11.2DS. We applied constrained principal component analysis to identify temporally overlapping brain activation patterns from BOLD fMRI data acquired during an emotion identification task from 58 individuals with 22q11.2DS and 58 age-, race-, and sex-matched healthy controls. Delayed frontal-motor feedback signals were diminished in individuals with 22q11.2DS, as were delayed emotional memory signals engaging amygdala, hippocampus, and entorhinal cortex. Early task-related engagement of motor and visual cortices and salience-related insular activation were relatively preserved in 22q11.2DS. Insular activation was associated with task performance within the 22q11.2DS sample. Differences in cortical surface area, but not cortical thickness, showed spatial alignment with an activation pattern associated with face processing. These findings suggest that relative to matched controls, primary visual processing and insular function are relatively intact in individuals with 22q11.22DS, while motor feedback, face processing, and emotional memory processes are more affected. Such insights may help inform potential interventional targets and enhance the specificity of neuroimaging indices of cognitive dysfunction in 22q11.2DS.

Development and application of novel performance validity metrics for computerized neurocognitive batteries.

OBJECTIVES: Data from neurocognitive assessments may not be accurate in the context of factors impacting validity, such as disengagement, unmotivated responding, or intentional underperformance. Performance validity tests (PVTs) were developed to address these phenomena and assess underperformance on neurocognitive tests. However, PVTs can be burdensome, rely on cutoff scores that reduce information, do not examine potential variations in task engagement across a battery, and are typically not well-suited to acquisition of large cognitive datasets. Here we describe the development of novel performance validity measures that could address some of these limitations by leveraging psychometric concepts using data embedded within the Penn Computerized Neurocognitive Battery (PennCNB). METHODS: We first developed these validity measures using simulations of invalid response patterns with parameters drawn from real data. Next, we examined their application in two large, independent samples: 1) children and adolescents from the Philadelphia Neurodevelopmental Cohort (n = 9498); and 2) adult servicemembers from the Marine Resiliency Study-II (n = 1444). RESULTS: Our performance validity metrics detected patterns of invalid responding in simulated data, even at subtle levels. Furthermore, a combination of these metrics significantly predicted previously established validity rules for these tests in both developmental and adult datasets. Moreover, most clinical diagnostic groups did not show reduced validity estimates. CONCLUSIONS: These results provide proof-of-concept evidence for multivariate, data-driven performance validity metrics. These metrics offer a novel method for determining the performance validity for individual neurocognitive tests that is scalable, applicable across different tests, less burdensome, and dimensional. However, more research is needed into their application.

Development of structure-function coupling in human brain networks during youth.

The protracted development of structural and functional brain connectivity within distributed association networks coincides with improvements in higher-order cognitive processes such as executive function. However, it remains unclear how white-matter architecture develops during youth to directly support coordinated neural activity. Here, we characterize the development of structure-function coupling using diffusion-weighted imaging and n-back functional MRI data in a sample of 727 individuals (ages 8 to 23 y). We found that spatial variability in structure-function coupling aligned with cortical hierarchies of functional specialization and evolutionary expansion. Furthermore, hierarchy-dependent age effects on structure-function coupling localized to transmodal cortex in both cross-sectional data and a subset of participants with longitudinal data (n = 294). Moreover, structure-function coupling in rostrolateral prefrontal cortex was associated with executive performance and partially mediated age-related improvements in executive function. Together, these findings delineate a critical dimension of adolescent brain development, whereby the coupling between structural and functional connectivity remodels to support functional specialization and cognition.

Regional White Matter Scaling in the Human Brain.

Anatomical organization of the primate cortex varies as a function of total brain size, where possession of a larger brain is accompanied by disproportionate expansion of associative cortices alongside a relative contraction of sensorimotor systems. However, equivalent scaling maps are not yet available for regional white matter anatomy. Here, we use three large-scale neuroimaging datasets to examine how regional white matter volume (WMV) scales with interindividual variation in brain volume among typically developing humans (combined N = 2391: 1247 females, 1144 males). We show that WMV scaling is regionally heterogeneous: larger brains have relatively greater WMV in anterior and posterior regions of cortical white matter, as well as the genu and splenium of the corpus callosum, but relatively less WMV in most subcortical regions. Furthermore, regions of positive WMV scaling tend to connect previously-defined regions of positive gray matter scaling in the cortex, revealing a coordinated coupling of regional gray and white matter organization with naturally occurring variations in human brain size. However, we also show that two commonly studied measures of white matter microstructure, fractional anisotropy (FA) and magnetization transfer (MT), scale negatively with brain size, and do so in a manner that is spatially unlike WMV scaling. Collectively, these findings provide a more complete view of anatomic scaling in the human brain, and offer new contexts for the interpretation of regional white matter variation in health and disease.SIGNIFICANCE STATEMENT Recent work has shown that, in humans, regional cortical and subcortical anatomy show systematic changes as a function of brain size variation. Here, we show that regional white matter structures also show brain-size related changes in humans. Specifically, white matter regions connecting higher-order cortical systems are relatively expanded in larger human brains, while subcortical and cerebellar white matter tracts responsible for unimodal sensory or motor functions are relatively contracted. This regional scaling of white matter volume (WMV) is coordinated with regional scaling of cortical anatomy, but is distinct from scaling of white matter microstructure. These findings provide a more complete view of anatomic scaling of the human brain, with relevance for evolutionary, basic, and clinical neuroscience.

Voxel-wise intermodal coupling analysis of two or more modalities using local covariance decomposition.

When individual subjects are imaged with multiple modalities, biological information is present not only within each modality, but also between modalities - that is, in how modalities covary at the voxel level. Previous studies have shown that local covariance structures between modalities, or intermodal coupling (IMCo), can be summarized for two modalities, and that two-modality IMCo reveals otherwise undiscovered patterns in neurodevelopment and certain diseases. However, previous IMCo methods are based on the slopes of local weighted linear regression lines, which are inherently asymmetric and limited to the two-modality setting. Here, we present a generalization of IMCo estimation which uses local covariance decompositions to define a symmetric, voxel-wise coupling coefficient that is valid for two or more modalities. We use this method to study coupling between cerebral blood flow, amplitude of low frequency fluctuations, and local connectivity in 803 subjects ages 8 through 22. We demonstrate that coupling is spatially heterogeneous, varies with respect to age and sex in neurodevelopment, and reveals patterns that are not present in individual modalities. As availability of multi-modal data continues to increase, principal-component-based IMCo (pIMCo) offers a powerful approach for summarizing relationships between multiple aspects of brain structure and function. An R package for estimating pIMCo is available at: https://github.com/hufengling/pIMCo.

Repeatability of B1 + inhomogeneity correction of volumetric (3D) glutamate CEST via High-permittivity dielectric padding at 7T.

PURPOSE: Ultra-high field MR imaging lacks B1 + inhomogeneity due to shorter RF wavelengths used at higher field strengths compared to human anatomy. CEST techniques tend to be highly susceptible to B1 + inhomogeneities due to a high and uniform B1 + field being necessary to create the endogenous contrast. High-permittivity dielectric pads have seen increasing usage in MR imaging due to their ability to tailor the spatial distribution of the B1 + field produced. The purpose of this work is to demonstrate that dielectric materials can be used to improve glutamate weighted CEST (gluCEST) at 7T. THEORY AND METHODS: GluCEST images were acquired on a 7T system on six healthy volunteers. Aqueous calcium titanate pads, with a permittivity of approximately 110, were placed on either side in the subject's head near the temporal lobes. A post-processing correction algorithm was implemented in combination with dielectric padding to compare contrast improvement. Tissue segmentation was performed to assess the effect of dielectric pads on gray and white matter separately. RESULTS: GluCEST images demonstrated contrast enhancement in the lateral temporal lobe regions with dielectric pad placement. Tissue segmentation analysis showed an increase in correction effectiveness within the gray matter tissue compared to white matter tissue. Statistical testing suggested a significant difference in gluCEST contrast when pads were used and showed a difference in the gray matter tissue segment. CONCLUSION: The use of dielectric pads improved the B1 + field homogeneity and enhanced gluCEST contrast for all subjects when compared to data that did not incorporate padding.

Diminished reward responsiveness is associated with lower reward network GluCEST: an ultra-high field glutamate imaging study.

Low reward responsiveness (RR) is associated with poor psychological well-being, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain's reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field glutamate chemical exchange saturation transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0 T from 45 participants (ages 15-29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up investigations identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

A systematic review and meta-analysis of intellectual, neuropsychological, and psychoeducational functioning in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder frequently associated with cognitive deficits. Despite cognitive deficits being a key feature of NF1, the profile of such impairments in NF1 has been shown to be heterogeneous. Thus, we sought to quantitatively synthesize the extant literature on cognitive functioning in NF1. A random-effects meta-analysis of cross-sectional studies was carried out comparing cognitive functioning of patients with NF1 to typically developing or unaffected sibling comparison subjects of all ages. Analyses included 50 articles (Total NNF1 = 1,522; MAge = 15.70 years, range = 0.52-69.60), yielding 460 effect sizes. Overall moderate deficits were observed [g = -0.64, 95% CI = (-0.69, -0.60)] wherein impairments differed at the level of cognitive domain. Deficits ranged from large [general intelligence: g = -0.95, 95% CI = (-1.12, -0.79)] to small [emotion: g = -0.37, 95% CI = (-0.63, -0.11)]. Moderation analyses revealed nonsignificant contributions of age, sex, educational attainment, and parental level of education to outcomes. These results illustrate that cognitive impairments are diffuse and salient across the lifespan in NF1. Taken together, these results further demonstrate efforts should be made to evaluate and address cognitive morbidity in patients with NF1 in conjunction with existing best practices.