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Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher order functions through various cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because acute pathology is not found in the cerebellum as often. Acute pathology is an important predictor of outcome, but neural disruption also evolves over time in ways that have implications for daily-life functioning. Here we examine these changes in a multi-modal, multi-cohort study.Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 ± 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (i.e., Behavioral Rating Inventory of Executive Function [BRIEF]). In a subsample with longitudinal data, we then assessed whether late changes in cerebellar volume were associated with early white matter microstructural organization using diffusion tensor imaging (DTI).Significantly smaller total cerebellar volume was observed in the msTBI group (Cohen’sd= −0.37). In addition, lower regional cerebellar volume was found in posterior lobe regions including crus II, lobule VIIB, lobule VIIIB, vermis VII, and IX (Cohen’sdrange = −0.22 to −0.43). Smaller cerebellum volumes were associated with more parent-reported executive function problems. These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). In a subset of participants with longitudinal data (n = 80), we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration in the form of volume reductions, and older participants showing disrupted development reflected in slower growth rates. Changes in total cerebellum volume over time were also associated with white matter microstructural organization in the first weeks and months post-injury, such that poorer white matter organization in the first months post-injury was associated with decreases in volume longitudinally.Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes as well as injury-specific associations between DTI measures and volume changes, is suggestive of secondary cerebellar atrophy, possibly related to supra-tentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for robust brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.

Studies of brain morphometry may illuminate the effects of pediatric mild traumatic brain injury (TBI; e.g., concussion). However, no published studies have examined cortical thickness in the early injury phases of pediatric mild TBI using an appropriate comparison group. The current study used an automated approach (i.e., FreeSurfer) to determine whether cortical thickness differed in children following a mild TBI or a mild orthopedic injury (OI), and to examine whether post-acute cortical thickness predicted post-acute and chronic post-concussive symptoms (PCS). Children ages 8.00-16.99 years with mild TBI (n = 136) or OI (n = 70) were recruited at emergency department visits to two children's hospitals, during which parents rated children's pre-injury symptoms retrospectively. Children completed a post-acute (3–24 days post-injury) assessment, which included a 3 Tesla MRI, and 3- and 6-month post-injury assessments. Parents and children rated PCS at each assessment. Cortical thickness was estimated using FreeSurfer. Linear mixed effects and multi-variable negative binomial regression models were used to test study aims, with false discovery rate (FDR) correction for multiple comparisons. Groups differed significantly on left parietal cortical thickness (TBI > OI) after FDR correction. Cortical thickness also varied by brain subregion and age, but not sex. Groups differed significantly on PCS post-acutely (TBI > OI), but not at 3 or 6 months. Right frontal thickness was positively related to post-acute PCS in both groups. Right cingulum thickness predicted chronic PCS in the OI group only. Results highlight the complexity of predicting outcomes of pediatric mild TBI from post-acute neuroimaging biomarkers.

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population, and specific developmental issues require a unique context since findings from adult research do not necessarily directly translate to children. Findings in pediatric cohorts tend to lag behind those in adult samples. This may be due, in part, both to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate/Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis of neuroimaging data. In this paper, we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. With the paucity of research studies examining neuroimaging biomarkers in pediatric patients with TBI and the challenges of recruiting large numbers of participants, collaborating to improve statistical power and to address technical challenges like lesions will significantly advance the field. We conclude with recommendations for future research in this field of study.

Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individualswith 22q11DS and 330matched healthy control subjects (age range, 6-56 years; 49% female). Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, 20.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, 20.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

22q11.2 deletion syndrome (22q11DS)—a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22—is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6–52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen’s d’s ranging from −0.9 to −1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers. Sin financiación 15.992 JCR (2020) Q1, 10/295 Biochemistry & Molecular Biology 5.071 SJR (2020) Q1, 5/85 Cellular and Molecular Neuroscience No data IDR 2020 UEM

ObjectiveOur study addressed aims (1) to test the hypothesis that moderate-severe traumatic brain injury (TBI) in pediatric patients is associated with widespread white matter (WM) disruption, (2) to test the hypothesis that age and sex affect WM organization after injury, and (3) to examine associations between WM organization and neurobehavioral outcomes.MethodsData from 10 previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Pediatric Moderate/Severe TBI (msTBI) working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.ResultsFive hundred seven children and adolescents (244 with complicated msTBI and 263 controls) were included. Patients were clustered into 3 postinjury intervals: acute/subacute, ConclusionsWM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically meaningful patient subtypes.

Annually, approximately 3 million children around the world experience traumatic brain injuries (TBIs), of which up to 20% are characterized as moderate to severe (msTBI) and/or have abnormal imaging findings. Affected children are vulnerable to long-term cognitive and behavioral dysfunction, as injury can disrupt or alter ongoing brain maturation. Post-injury outcomes are highly variable, and there is only limited understanding of how inter-individual differences in outcomes arise. Small sample sizes have also complicated efforts to better understand factors influencing the impact of TBI on the developing brain. White matter (WM) disruption is a critical aspect of TBI neuropathology and diffusion MRI (dMRI) is particularly sensitive to microstructural abnormalities. Here we present the results of a coordinated analysis of dMRI data across ten cohorts from three countries. We had three primary aims: (1) to characterize the nature and extent of WM disruption across key post-injury intervals (acute/subacute - within 2 months, post-acute - 2-6 months, chronic - 6+ months); (2) evaluate the impact of age and sex on WM in the context of injury; and (3) to examine associations between WM and neurobehavioral outcomes. Based on data from 507 children and adolescents (244 with complicated mild to severe TBI and 263 control children), we report widespread WM disruption across all post-injury intervals. As expected, injury severity was a significant contributor to the pattern and extent of WM degradation, but explained less variance in dMRI measures with increasing time since injury, supporting other research indicating that other factors contribute increasingly to outcomes over time. The corpus callosum appears to be particularly vulnerable to injury, an effect that persists years post-TBI. We also report sex differences in the effect of TBI on the uncinate fasciculus (UNC), a structure with a key role in emotion regulation. Females with a TBI had significantly lower fractional anisotropy (FA) in the UNC than those with no TBI, and this phenomenon was further associated with more frequent parent-reported behavioral problems as measured by the Child Behavior Checklist (CBCL). These effects were not detected in males. With future harmonization of imaging and neurocognitive data, more complex modeling of factors influencing outcomes will be possible and help to identify clinically-meaningful patient subtypes.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Objectives Pediatric Obstructive Sleep Apnea (OSA) is associated with neurocognitive deficits. Cerebral structural alterations in the frontal cortex, cerebellum, and hippocampus have been reported in adult OSA patients. These brain areas are important for executive functioning, motor regulation of breathing, and memory function, respectively. Corresponding evidence comparing cerebral structures in pediatric OSA patients is limited. The objective of this study is to investigate MRI differences in cortical thickness and cortical volume in children with and without OSA. Study design Prospective, single institutional case-control study. Methods Forty-five children were recruited at a pediatric tertiary care center (27 with OSA; mean age 9.9 ± 1.9 years, and 18 controls; mean age 10.5 ± 1.0 years). The OSA group underwent magnetic resonance imaging (MRI), polysomnography (PSG) and completed the Pediatric Daytime Sleepiness Scale (PDSS) and the Child's Sleep Habits Questionnaire (CSHQ). High-resolution T1-weighted MRI was utilized to examine cortical thickness and gray and white matter volume in children with OSA compared to a healthy group of demographically-comparable children without OSA selected from a pre-existing MRI dataset. Results Children with OSA showed multiple regions of cortical thinning primarily in the left hemisphere. Reduced gray matter (GM) volume was noted in the OSA group in multiple frontal regions of the left hemisphere (superior frontal, rostral medial frontal, and caudal medial frontal regions). Reduced white matter (WM) volume in both the left and right hemisphere was observed in regions of the frontal, parietal, and occipital lobes in children with OSA. Conclusion This study noted differences in cortical thickness and GM and WM regional brain volumes in children with OSA. These findings are consistent with other pediatric studies, which also report differences between healthy children and those with OSA. We found that the severity of OSA does not correlate with the extent of MRI alterations.

This investigation explored whether differences in cortical thickness could be detected in children who sustained a mild traumatic brain injury (mTBI) compared to those with orthopedic injury (OI) and whether cortical thickness related parental reporting of symptoms. To achieve this objective, FreeSurfer®-based cortical thickness measures were obtained in 330 children, 8 to 15 years of age, with either a history of mTBI or OI. Imaging was performed in all participants with the same 3 Tesla MRI scanner at six-months post-injury, where a parent-rated Post-Concussion Symptom Inventory (PCSI) was also obtained. Robust age-mediated reductions in cortical thickness were observed, but no consistent group-based differences between the mTBI and OI groups were observed. Also, the relation between mechanism of injury (i.e., sports-related, recreational, fall, motor vehicle accident or other) and cortical thickness was examined. Injuries associated with any type of abuse were excluded and children with OI could not have experienced a MVA. Mechanism of injury did not differentially relate to cortical thickness, although in the fall group, parental rating using the PCSI showed increased symptom reporting to be associated with reduced cortical thickness in the left interior frontal, temporal pole and lateral temporal lobe as well as in the right temporal pole. Results from these preliminary findings are discussed in terms of injury variables and developmental factors associated with mTBI in childhood.

Occurring in at least 1 in 3,000 live births, chromosome 22q11.2 deletion syndrome (22q11DS) produces a complex phenotype that includes a constellation of medical complications such as congenital cardiac defects, immune deficiency, velopharyngeal dysfunction, and characteristic facial dysmorphic features. There is also an increased incidence of psychiatric diagnosis, especially intellectual disability and ADHD in childhood, lifelong anxiety, and a strikingly high rate of schizophrenia spectrum disorders, which occur in around 30% of adults with 22q11DS. Using innovative computational connectomics, we studied how 22q11DS affects high-level network signatures of hierarchical modularity and its intrinsic geometry in 55 children with confirmed 22q11DS and 27 Typically Developing (TD) children. Results identified 3 subgroups within our 22q11DS sample using a K-means clustering approach based on several midline structural measures-of-interests. Each subgroup exhibited distinct patterns of connectome abnormalities. Subtype 1, containing individuals with generally healthy-looking brains, exhibited no significant differences in either modularity or intrinsic geometry when compared with TD. By contrast, the more anomalous 22q11DS Subtypes 2 and 3 brains revealed significant modular differences in the right hemisphere, while Subtype 3 (the most anomalous anatomy) further exhibited significantly abnormal connectome intrinsic geometry in the form of left-right temporal disintegration. Taken together, our findings supported an overall picture of (a) anterior-posteriorly differential interlobar frontotemporal/frontoparietal dysconnectivity in Subtypes 2 and 3 and (b) differential intralobar dysconnectivity in Subtype 3. Our ongoing studies are focusing on whether these subtypes and their connnectome signatures might be valid biomarkers for predicting the degree of psychosis-proneness risk found in 22q11DS. Hum Brain Mapp 39:232-248, 2018. © 2017 Wiley Periodicals, Inc.

Although there are several techniques to analyze diffusion-weighted imaging, any technique must be sufficiently sensitive to detect clinical abnormalities. This is especially critical in disorders like mild traumatic brain injury (mTBI), where pathology is likely to be subtle. mTBI represents a major public health concern, especially for youth under 15 years of age. However, the developmental period from birth to 18 years is also a time of tremendous brain changes. Therefore, it is important to establish the degree of age- and sex-related differences. Participants were children aged 8–15 years with mTBI or mild orthopedic injuries (OI). Imaging was obtained within 10 days of injury. We performed tract-based spatial statistics (TBSS), deterministic tractography using AFQ (Automated Fiber Quantification), and probabilistic tractography using TRACULA (TRActs Constrained by UnderLying Anatomy) to evaluate whether any method provided improved sensitivity at identifying group, developmental, and/or sex-related differences. Although, there were no group differences from any of the three analyses, many of the tracts, but not all, revealed increases of fractional anisotropy (FA) and decreases of axial, radial, and mean diffusivity (AD, RD, and MD, respectively) with age. TBSS analyses resulted in age-related changes across all white matter tracts. AFQ and TRACULA revealed age-related changes within the corpus callosum, cingulum cingulate, corticospinal tract, inferior and superior longitudinal fasciculus, and uncinate fasciculus. The results are in many ways consistent across all three methods. However, results from the tractography methods provided improved sensitivity and better tract-specific results for identifying developmental and sex-related differences within the brain.

Introduction: Mild traumatic brain injury (TBI) is a global public health concern that affects millions of children annually. Mild TBI tends to result in subtle and diffuse alterations in brain tissue, which challenges accurate clinical detection and prognostication. Diffusion tensor imaging (DTI) holds promise as a diagnostic and prognostic tool, but little research has examined DTI in post-acute mild TBI. The current study compared post-acute white matter microstructure in children with mild TBI versus those with mild orthopedic injury (OI), and examined whether post-acute DTI metrics can predict post-acute and chronic post-concussive symptoms (PCS). Materials and methods: Children aged 8–16.99 years with mild TBI (n = 132) or OI (n = 69) were recruited at emergency department visits to two children's hospitals, during which parents rated children's pre-injury symptoms retrospectively. Children completed a post-acute (

Structural and functional connectivity (FC) after sports-related concussion (SRC) may remain altered in adolescent athletes despite symptom resolution. Little is known, however, about how alterations in structural connectivity and FC co-present in female athletes whose symptom recovery tends to be prolonged. Despite resolution of symptoms, one month after her second SRC, an 18-year-old female athlete had decreased structural connectivity in the corpus callosum and cingulum, with altered FC near those regions, compared with other SRC and orthopedically injured athletes. Findings show persistent effects of SRC on advanced brain imaging and the possibility of greater vulnerability of white matter tracts in females.

Objectives The chronic effects of neurotrauma consortium (CENC) observational study is a multisite investigation designed to examine the long-term longitudinal effects of mild traumatic brain injury (mTBI). All participants in this initial CENC cohort had a history of deployment in Operation Enduring Freedom (Afghanistan), Operation Iraqi Freedom (Iraq), and/or their follow-on conflicts (Operation Freedom's Sentinel). All participants undergo extensive medical, neuropsychological, and neuroimaging assessments and either meet criteria for any lifetime mTBI or not. These assessments are integrated into six CENC core studies-Biorepository, Biostatistics, Data and Study Management, Neuroimaging, and Neuropathology. Methods The current study outlines the quantitative neuroimaging methods managed by the Neuroimaging Core using FreeSurfer automated software for image quantification. Results At this writing, 319 participants from the CENC observational study have completed all baseline assessments including the imaging protocol and tertiary data quality assurance procedures. Conclusions/discussion The preliminary findings of this initial cohort are reported to describe how the Neuroimaging Core manages neuroimaging quantification for CENC studies.

An important component of the multicentre Chronic Effects of Neurotrauma Consortium (CENC) project is the development of improved quantitative magnetic resonance imaging (MRI) methods, including volumetric analysis. Although many studies routinely employ quality assurance (QA) procedures including MR and human phantoms to promote accuracy and monitor site differences, few studies perform rigorous direct comparisons of these data nor report findings that enable inference regarding site-to-site comparability. These gaps in evaluating cross-site differences are concerning, especially given the well-established differences that can occur between data acquired on scanners with different manufacturer, hardware or software.This study reports findings on (1) a series of studies utilizing two MR phantoms to interrogate machine-based variability using data collected on the same magnet, (2) a human phantom repeatedly imaged on the same scanner to investigate within-subject, within-site variability and (3) a human phantom imaged on three different scanners to examine within subject, between-site variability.Although variability is relatively minimal for the phantom scanned on the same magnet, significantly more variability is introduced in a human subject, particularly when regions are relatively small or multiple sites used.Vigilance when combining data from different sites is suggested and that future efforts address these issues.

In a sample of children with traumatic brain injury, this magnetic resonance imaging (MRI)–based investigation examined whether presence of a focal lesion uniquely influenced cortical thickness in any brain region. Specifically, the study explored the relation of cortical thickness to injury severity as measured by Glasgow Coma Scale score and length of stay, along with presence of encephalomalacia, focal white matter lesions or presence of hemosiderin deposition as a marker of shear injury. For comparison, a group of children without head injury but with orthopedic injury of similar age and sex were also examined. Both traumatic brain injury and orthopedic injury children had normally reduced cortical thickness with age, assumed to reflect neuronal pruning. However, the reductions observed within the traumatic brain injury sample were similar to those in the orthopedic injury group, suggesting that in this sample traumatic brain injury, per se, did not uniquely alter cortical thickness in any brain region at the group level. Injury severity in terms of Glasgow Coma Scale or longer length of stay was associated with greater reductions in frontal and occipitoparietal cortical thickness. However, presence of focal lesions were not related to unique changes in cortical thickness despite having a prominent distribution of lesions within frontotemporal regions among children with traumatic brain injury. Because focal lesions were highly heterogeneous, their association with cortical thickness and development appeared to be idiosyncratic, and not associated with group level effects.

Author(s): Scott, Julia A; Goodrich-Hunsaker, Naomi; Kalish, Kristopher; Lee, Aaron; Hunsaker, Michael R; Schumann, Cynthia M; Carmichael, Owen T; Simon, Tony J | Abstract: BackgroundIndividuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population.MethodsWe measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety.ResultsWe included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group.LimitationsShape alterations are not specific to hippocampal subfields.ConclusionAlterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection.

Diffusion MRI (dMRI) is widely used to study the brain’s white matter (WM) microstructure in a range of psychiatric and neurological diseases. As the diffusion tensor model has limitations in brain regions with crossing fibers, novel diffusion MRI reconstruction models may offer more accurate measures of tissue properties, and a better understanding of the brain abnormalities in specific diseases. Here we studied a large sample of 249 participants with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with high rates of developmental neuropsychiatric disorders, and 224 age-matched healthy controls (HC) (age range: 8-35 years). Participants were scanned with dMRI at eight centers worldwide. Using a meta-analytic approach, we assessed the profile of group differences in four diffusion anisotropy measures to better understand the patterns of WM microstructural abnormalities and evaluate their consistency across alternative measures. When assessed in atlas-defined regions of interest, we found statistically significant differences for all anisotropy measures, all showing a widespread but not always coinciding pattern of effects. The tensor distribution function fractional anisotropy (TDF-FA) showed largest effect sizes all in the same direction (greater anisotropy in 22q11DS than HC). Fractional anisotropy based on the tensor model (FA) showed the second largest effect sizes after TDF-FA; some regions showed higher mean values in 22q11DS, but others lower. Generalized fractional anisotropy (GFA) showed the opposite pattern to TDF-FA with most regions showing lower anisotropy in 22q11DS versus HC. Anisotropic power maps (AP) showed the lowest effect sizes also with a mixed pattern of effects across regions. These results were also consistent across skeleton projection methods, with few differences when projecting anisotropy values from voxels sampled on the FA map or projecting values from voxels sampled from each anisotropy map. This study highlights that different mathematical definitions of anisotropy may lead to different profiles of group differences, even in large, well-powered population studies. Further studies of biophysical models derived from multi-shell dMRI and histological validations may help to understand the sources of these differences. 22q11DS is a promising model to study differences among novel anisotropy/dMRI measures, as group differences are relatively large and there exist animal models suitable for histological validation.

Fragile X premutation carriers (fXPC) are characterized by 55-200 CGG trinucleotide repeats in the 5' untranslated region on the Xq27.3 site of the X chromosome. Clinically, they are associated with the fragile X-Associated Tremor/Ataxia Syndrome, a late-onset neurodegenerative disorder with diffuse white matter neuropathology. Here, we conducted first-ever graph theoretical network analyses in fXPCs using 30-direction diffusion-weighted magnetic resonance images acquired from 42 healthy controls aged 18-44 years (HC; 22 male and 20 female) and 46 fXPCs (16 male and 30 female). Globally, we found no differences between the fXPCs and HCs within each gender for all global graph theoretical measures. In male fXPCs, global efficiency was significantly negatively associated with the number of CGG repeats. For nodal measures, significant group differences were found between male fXPCs and male HCs in the right fusiform and the right ventral diencephalon (for nodal efficiency), and in the left hippocampus [for nodal clustering coefficient (CC)]. In female fXPCs, CC in the left superior parietal cortex correlated with counting performance in an enumeration task.

Common neuroimaging findings in mild traumatic brain injury (mTBI), including sport-related concussion (SRC), are reviewed based on computed tomography and magnetic resonance imaging (MRI). Common abnormalities radiologically identified on the day of injury, typically a computed tomographic scan, are in the form of contusions, small subarachnoid or intraparenchymal hemorrhages as well as subdural and epidural collections, edema, and skull fractures. Common follow-up neuroimaging findings with MRI include white matter hyperintensities, hypointense signal abnormalities that reflect prior hemorrhage, focal encephalomalacia, presence of atrophy and/or dilated Virchow-Robins perivascular space. The MRI findings from a large pediatric mTBI study show low frequency of positive MRI findings at 6 months postinjury. The review concludes with an examination of some of the advanced MRI-based image analysis methods that can be performed in the patient who has sustained an mTBI.

Computational models of hippocampal function propose that the hippocampus is capable of rapidly storing distinct representations through a process known as pattern separation. This prediction is supported by electrophysiological data from rodents and neuroimaging data from humans. Here, we test the prediction that damage to the hippocampus would result in pattern separation deficits by having memory-impaired patients with bilateral hippocampal damage study a series of objects or faces and then perform a modified recognition memory test. In the test phase, participants viewed true repetitions, novel foils, and lures that were perceptually and semantically related to the studied stimuli. Patients with hippocampal damage were unimpaired relative to matched controls in their baseline recognition memory. However, patients were less likely to uniquely identify lures as "similar" than matched controls, indicating an impairment in pattern separation processes following damage to the hippocampus.

A previous study reported preliminary results of enhanced processing of simple visual information in the form of faster reaction times, in female fragile X premutation carriers (fXPCs). In this study, we assessed manual and oral motor reaction times in 30 female fXPCs and 20 neurotypical (NT) controls. Participants completed two versions of the reaction time task; one version required a manual motor response and the other version required an oral motor response. Results revealed that the female fXPCs displayed faster reaction times for both manual and oral motor responses relative to NT controls. Molecular measures including CGG repeat length, FMR1 mRNA levels, and age were not associated with performance in either group. Given previously reported age and CGG repeat modulated performance on a magnitude comparison task in this same group of premutation carriers, results from the current study seem to suggest that female fXPCs may have spared basic psychomotor functionality. (JINS, 2011, 17, 746–750)

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG trinucleotide repeat lengths between 70 and 350 has been developed and used to model the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial and temporal information. To characterize the motor deficits associated with the fragile X premutation, male and female CGG KI mice ranging from 2 to 16 months of age with trinucleotide repeats ranging from 72 to 240 CGG in length were tested for their ability to perform a skilled ladder rung walking test. The results demonstrate that both male and female CGG KI mice showed a greater number of foot slips as a function of increased CGG repeat length, independent of the age of the animal or general activity level. (C) 2011 Elsevier B.V. All rights reserved.

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG repeat lengths between 70 and 350 has been developed and used to characterize the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG Kt mice show progressive deficits in processing spatial information. To further characterize cognitive deficits in the fragile X premutation, temporal ordering in CGG knock-in (CGG KI) mice was evaluated. Female CGG KI mice were tested for their ability to remember the temporal order in which two objects were presented. The results demonstrate that at 48 weeks of age, female CGG KI mice with CGG repeat expansions between 150 and 200 CGG repeats performed more poorly on tests of temporal order than wildtype mice, whereas female CGG Kt mice with between 80 and 100 CGG repeats performed similarly to wildtype mice. No mice had any difficulty in detecting the presence of a novel object. These data suggest female CGG KI mice show a CGG repeat length-sensitive deficit for temporal ordering. (C) 2010 Elsevier B.V. All rights reserved.

The Word Memory Test (WMT) is a commonly used symptom validity test (SVT) that assesses recognition verbal memory. The task has been adapted for use within a functional magnetic resonance imaging (fMRI) paradigm so the neural correlates of WMT activation patterns can be studied. In the current investigation, performance on the delayed recognition subtest of the WMT was examined in two patients who sustained severe TBI and compared to ten healthy controls. The patients underwent comprehensive neuropsychological evaluations and structural MRI. All participants completed two versions of the WMT: full-effort and simulated poor effort conditions. Despite extensive structural brain damage, the fMRI activation patterns during full-effort WMT performance were somewhat similar in the two TBI patients and likewise, somewhat similar to controls. The fMRI activation pattern in both patients demonstrated intact activation of the basic neural structures necessary to perform the WMT. Dissimilar patterns of activation were obtained during the simulated poor effort condition of WMT performance suggesting that fMRI techniques may be sensitive in demonstrating non-credible cognitive performance. The results of our study represent the first fMRI investigation of normal and simulated poor effort SVT performance in individuals with documented brain damage. The implications of fMRI techniques in SVT research and their clinical application are discussed.

The Word Memory Test (WMT) is a popular symptom validity test in which individuals are required to remember and recall semantically-related word pairs. Research shows successful WMT completion employs a wide neural network which is involved in tasks requiring high cognitive effort. The primary purpose of this study was to replicate earlier fMRI findings using a larger sample and extend previous findings by including male and female subjects. The second purpose was to investigate the neural networks involved during intentional malingering on the WMT.For all trials, a time-series ANCOVA design was implemented using SPM5 software.Ten subjects (five male and five female) underwent fMRI imaging while completing the WMT in full-effort and simulated poor effort conditions.Full-effort trials found activation peaks in dorsolateral prefrontal cortex, superior parietal lobe, anterior cingulate, bilateral lingual cortices and anterior insula/frontal operculum, supporting earlier findings. Simulated poor effort trials had similar foci of activation, with additional peak strength in surrounding cortical regions identified previously as relevant to simulated malingering. No sex differences were observed in either condition.These findings demonstrate the neural underpinnings of WMT performance in normal and simulated performance.

Several studies have demonstrated the significance of a spatial cognitive map and its role for guided and accurate navigation through the environment. Learning and recalling spatial knowledge depends upon proper topological and metric spatial information processing. The present objectives are to better characterize the role of the hippocampus for processing topological and metric spatial information. Rats with dorsal hippocampal subregional lesions (dDG, dCA3, dCA1) were tested on a previously established metric task and topological task. The results of the present study suggest that dCA1, but not dDG or dCA3, mediates topological memory. Furthermore, dDG, dCA3, and dCA1 mediate metric memory. Dorsal DG is required for spatial information processing via pattern separation or orthogonalization of sensory inputs to generate metric representations. Dorsal CA3 and dCA1 then receive these metric representations transmitted from dDG along the trisynaptic loop. The present data add to a growing body of literature suggesting a diversity of function among the hippocampal subregions.

This study presents data from a functional neuroimaging experiment which brings into question whether poor performance on the Word Memory Test (WMT) can be construed as straightforward evidence for 'poor effort' in the context of cognitive assessment, as asserted in a recent report in this journal.Functional magnetic resonance image (fMRI) data were acquired from four participants without brain injury who engaged in the delayed recognition (DR) portion of Green's WMT protocol.Compared to a simple perceptual identification control task, this study found a highly reliable activation pattern across all participants which was restricted almost exclusively to cortical areas most commonly associated with task difficulty, memory load, concentration and other forms of cognitive effort These areas include dorsolateral prefrontal cortex, anterior insula, superior parietal cortex and the dorsal anterior cingulate.These findings demonstrate that the WMT activates numerous cortical regions that are critical for cognitive effort. Given the extensive neural network necessary to perform the WMT, this study raises important questions about what WMT 'failure' truly means in patients with traumatic brain injury, who have increased likelihood of disruption within this neural network of vision, language, attention, effort and working memory.

Extensive research indicates that the hippocampus is crucial for the formation and use of memory in humans. Memory is extremely complex in terms of the kind of information that is represented in the brain, the processes associated with it, and its distribution across a variety of neural systems. While most investigators agree that the hippocampus is an essential neural structure involved in memory, debate remains regarding the exact information the hippocampus processes such as temporal, spatial, sensory (e.g., odors, objects, sounds, etc.), response, reward, linguistic, and relational information. In the context of the Attribute Model of Memory, this chapter will discuss the effects of hippocampal damage on memory in humans based on findings from behavioral and neuroimaging studies.

Dorsal hippocampus, parietal cortex, and control lesioned rats were tested on both a metric and topological task. The metric task consisted of 2 different objects placed 68 cm apart on a cheese board. After habituation, the objects were moved to a separation of 38 cm on Day 1 and to a separation of 98 cm on Day 2. The topological task consisted of 4 different objects placed in a square orientation. After habituation, the first 2 objects were switched, and after the rats habituated to that change, the back 2 objects were switched. This was repeated on a different day with 4 new objects. The data suggest that the hippocampus is necessary for metric representations, whereas the parietal cortex is necessary for topological representations.

© 2015 Elsevier Ireland Ltd. The fornix is the primary subcortical output fiber system of the hippocampal formation. In children with 22q11.2 deletion syndrome (22q11.2DS), hippocampal volume reduction has been commonly reported, but few studies as yet have evaluated the integrity of the fornix. Therefore, we investigated the fornix of 45 school-aged children with 22q11.2DS and 38 matched typically developing (TD) children. Probabilistic diffusion tensor imaging (DTI) tractography was used to reconstruct the body of the fornix in each child[U+05F3]s brain native space. Compared with children, significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) was observed bilaterally in the body of the fornix in children with 22q11.2DS. Irregularities were especially prominent in the posterior aspect of the fornix where it emerges from the hippocampus. Smaller volumes of the hippocampal formations were also found in the 22q11.2DS group. The reduced hippocampal volumes were correlated with lower fornix FA and higher fornix RD in the right hemisphere. Our findings provide neuroanatomical evidence of disrupted hippocampal connectivity in children with 22q11.2DS, which may help to further understand the biological basis of spatial impairments, affective regulation, and other factors related to the ultra-high risk for schizophrenia in this population.

Objective: Fragile X premutation carriers (fXPCs) have an expansion of 55 -200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (FXTAS) often accompanied by inhibitory control impairments, even in fXPCs without motor symptoms. Inhibitory control impairments might precede, and thus indicate elevated risk for motor impairment associated with FXTAS. We tested whether inhibitory impairments are observable in fXPCs by assessing oculomotor performance. Method: Participants were males aged 18-48 years asymptomatic for FXTAS. FXPCs (n = 21) and healthy age-matched controls (n = 22) performed four oculomotor tasks. In a Fixation task, participants fixated on a central cross and maintained gaze position when a peripheral stimulus appeared. In a Pursuit task, participants maintained gaze on a square moving at constant velocity. In a Prosaccade task, participants fixated on a central cross, then looked at a peripheral stimulus. An Antisaccade task was identical to the Prosaccade task, except participants looked in the direction opposite the stimulus. Inhibitory cost was the difference in saccade latency between the Antisaccade and Prosaccade tasks. Results: Relative to controls, fXPCs had longer saccade latency in the Antisaccade task. In fXPCs, inhibitory cost was positively associated with vermis area in lobules VI-VII. Conclusion: Antisaccades require inhibitory control to inhibit reflexive eye movements. We found that eye movements are sensitive to impaired inhibitory control in fXPCs asymptomatic for FXTAS. Thus, eye movements may be useful in assessing FXTAS risk or disease progression. © 2014 American Psychological Association.

Background A previous study reported enhanced psychomotor speed, and subtle but significant cognitive impairments, modulated by age and by mutations in the fragile X mental retardation 1 (FMR1) gene in adult female fragile X premutation carriers (fXPCs). Because male carriers, unlike females, do not have a second, unaffected FMR1 allele, male fXPCs should exhibit similar, if not worse, impairments. Understanding male fXPCs is of particular significance because of their increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS). Methods Male fXPCs (n = 18) and healthy control (HC) adults (n = 26) aged less than 45 years performed two psychomotor speed tasks (manual and oral) and two visuospatial tasks (magnitude comparison and enumeration). In the magnitude comparison task, participants were asked to compare and judge which of two bars was larger. In the enumeration task, participants were shown between one and eight green bars in the center of the screen, and asked to state the total number displayed. Enumeration typically proceeds in one of two modes: subitizing, a fast and accurate process that works only with a small set of items, and counting, which requires accurate serial-object detection and individuation during visual search. We examined the associations between the performance on all tasks and the age, full-scale intelligent quotient, and CGG repeat length of participants. Results We found that in the magnitude comparison and enumeration tasks, male fXPCs exhibited slower reaction times relative to HCs, even after controlling for simple reaction time. Conclusions Our results indicate that male fXPCs as a group show impairments (slower reaction times) in numerical visuospatial tasks, which are consistent with previous findings. This adds to a growing body of literature characterizing the phenotype in fXPCs who are asymptomatic for FXTAS. Future longitudinal studies are needed to determine how these impairments relate to risk of developing FXTAS.

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.

Extensive research with laboratory animals indicates that the hippocampus is crucial for the formation and use of spatial memory. Hippocampal lesions in rodents impair spatial memory on radial arm maze tasks. It is unknown whether amnesic patients with hippocampal damage would exhibit similar impairments on a virtual version of a radial arm maze. To evaluate the importance of the hippocampus in spatial learning and memory, we tested amnesic participants with hippocampal damage in a virtual radial arm maze environment. The virtual radial arm maze required participants to learn and remember 4 rewarded arms of 8 total arms. Spatial learning and memory were assessed using the participants' ability to use salient distal cues in the virtual room to remember the 4 rewarded arms. Amnesic participants' latencies were longer and distance traveled was greater to the rewarded arms compared with nonamnesic participants. Amnesic participants made more errors than nonamnesic participants by either entering nonrewarded arms or by revisiting previously entered arms. These data are analogous to previous animal research. Overall, the human hippocampus is necessary for spatial memory and navigation in a virtual radial arm maze task.

Many symptom validity tests (SVTs) assess performance validity via declarative memory paradigms. One widely used SVT, the Word Memory Test (WMT), uses a variety of memory tests to assess performance. It is well known that declarative memory requires the hippocampus and related medial temporal lobe structures. In the present study, WMT performance was examined in nonlitigating amnesic subjects (n = 3) with well-documented focal bilateral hippocampal atrophy who were nondemented and otherwise cognitively unimpaired compared with matched controls. The amnesic subjects had no external incentives. Amnesic subjects performed significantly below the level of matched comparison subjects but above established cutoff scores on the immediate recognition and delay recognition subtests and consistency component. In contrast, the amnesic subjects were impaired relative to our comparison subjects on the multiple-choice, paired associate, free-recall, and long delay free-recall subtests and had extremely low performance on these measures. Thus, there was a differential effect of hippocampal damage on WMT performance where the recognition subtests were performed within the normal range, yet the free recall was profoundly impaired in amnesic subjects. Such an approach where SVT performance is assessed in populations with well-known cognitive impairments adds breadth to SVT clinical interpretations.

This review summarizes a series of experiments aimed at answering the question whether the hippocampus in rats can serve as an animal model of amnesia. It is recognized that a comparison of the functions of the rat hippocampus with human hippocampus is difficult, because of differences in methodology, differences in complexity of life experiences, and differences in the degree of hippocampal damage. Notwithstanding, rats and humans with hippocampal damage are similarly impaired on analogous tasks that assess spatial memory, spatial pattern separation, spatial configural and arbitrary associations, temporal order memory, temporal pattern separation, sequential learning, and temporal associations. These data suggest that the rat can serve as a model of memory dysfunction (amnesia) as it relates to spatial and temporal processing of new information.

Hippocampal lesions in rodents impair both object–place and odor–place associative memory. Subjects with hippocampal damage have impaired associative memory such as object–place memory. Whereas studies have investigated some types of associative memory, no investigation has specifically examined odor–place associative memory in subjects with well-defined amnesia. It is unknown whether amnesic subjects with hippocampal damage would be impaired on an odor–place associative task. We investigated the effect of hippocampal damage in amnesic subjects with hippocampal atrophy on odor–place associative memory and recognition memory tasks. Amnesic and healthy comparison subjects matched for age and education were tested on an odor–place associative task, an odor recognition task, and a place recognition task. The odor–place associative task required subjects to associate 6 odors with 6 spatial locations on a board. The recognition tasks required subjects to identify the 6 odors and the 6 locations that were presented during the associative task. Amnesic subjects were impaired for odor–place memory and place recognition, but not odor recognition compared with comparison subjects. These results suggest that the human hippocampus is necessary for odor–place associative memory and spatial recognition memory. These data provide support for the idea that odor–place associative memory is mediated by the hippocampus in both humans and rodents, suggesting an evolutionary continuity in cognitive function assigned to the hippocampus.

The Morris water maze is a standard paradigm for the testing of hippocampal function in laboratory animals. Virtual versions of the Morris water maze are now available and can be used to assess spatial learning and memory ability in both healthy and brain injured participants. To evaluate the importance of the hippocampus in spatial learning and memory, we tested five amnesic participants with selective hippocampal damage using a virtual water maze called the Arena Maze. The amnesic participants with hippocampal damage were impaired on the invisible platform (place) task that required them to use distal cues, but were able to navigate almost as well as comparison participants when the invisible platform was marked by a single proximal cue. These results not only confirm that the hippocampus plays a necessary role in human navigation in large-scale environments but also provides a new link between the mnemonic and navigational roles of the hippocampus. V C 2009 Wiley-Liss, Inc.

© 2014 Wong et al.; licensee BioMed Central. Background: Fragile X premutation carriers (fXPCs) have an expansion of 55-200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (fragile X-associated tremor/ataxia syndrome (FXTAS)) often accompanied by cognitive decline. Several broad domains are implicated as core systems of dysfunction in fXPCs, including perceptual processing of spatial information, orienting of attention to space, and inhibiting attention to irrelevant distractors. We tested whether orienting of spatial attention is impaired in fXPCs. Methods: Participants were fXPCs or healthy controls (HCs) asymptomatic for FXTAS. In experiment 1, they were male and female children and adults (aged 7-45 years). They oriented attention in response to volitional (endogenous) and reflexive (exogenous) cues. In experiment 2, the participants were men (aged 18-48 years). They oriented attention in an endogenous cueing task that manipulated the amount of information in the cue. Results: In women, fXPCs exhibited slower reaction times than HCs in both the endogenous and exogenous conditions. In men, fXPCs exhibited slower reaction times than HCs in the exogenous condition and in the challenging endogenous cueing task with probabilistic cues. In children, fXPCs did not differ from HCs. Conclusions: Because adult fXPCs were slower even when controlling for psychomotor speed, results support the interpretation that a core dysfunction in fXPCs is the allocation of spatial attention, while perceptual processing and attention orienting are intact. These findings indicate the importance of considering age and sex when interpreting and generalizing studies of fXPCs.