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A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap—namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?, NIH (Grant R01 EB020740)

A functional region of left fusiform gyrus termed “the visual word form area” (VWFA) develops during reading acquisition to respond more strongly to printed words than to other visual stimuli. Here, we examined responses to letters among 5- and 6-year-old early kindergarten children (N = 48) with little or no school-based reading instruction who varied in their reading ability. We used functional magnetic resonance imaging (fMRI) to measure responses to individual letters, false fonts, and faces in left and right fusiform gyri. We then evaluated whether signal change and size (spatial extent) of letter-sensitive cortex (greater activation for letters versus faces) and letter-specific cortex (greater activation for letters versus false fonts) in these regions related to (a) standardized measures of word-reading ability and (b) signal change and size of face-sensitive cortex (fusiform face area or FFA; greater activation for faces versus letters). Greater letter specificity, but not letter sensitivity, in left fusiform gyrus correlated positively with word reading scores. Across children, in the left fusiform gyrus, greater size of letter-sensitive cortex correlated with lesser size of FFA. These findings are the first to suggest that in beginning readers, development of letter responsivity in left fusiform cortex is associated with both better reading ability and also a reduction of the size of left FFA that may result in right-hemisphere dominance for face perception., Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant R01HD067312), National Institutes of Health (Grant R01HD067312)

Identification of specific neurophysiological dysfunctions resulting in selective reading difficulty (dyslexia) has remained elusive. In addition to impaired reading development, individuals with dyslexia frequently exhibit behavioral deficits in perceptual adaptation. Here, we assessed neurophysiological adaptation to stimulus repetition in adults and children with dyslexia for a wide variety of stimuli, spoken words, written words, visual objects, and faces. For every stimulus type, individuals with dyslexia exhibited significantly diminished neural adaptation compared to controls in stimulus-specific cortical areas. Better reading skills in adults and children with dyslexia were associated with greater repetition-induced neural adaptation. These results highlight a dysfunction of rapid neural adaptation as a core neurophysiological difference in dyslexia that may underlie impaired reading development. Reduced neurophysiological adaptation may relate to prior reports of reduced behavioral adaptation in dyslexia and may reveal a difference in brain functions that ultimately results in a specific reading impairment., NIH (Grant UL1RR025758)

Research suggests that early identification of developmental dyslexia is important for mitigating the negative effects of dyslexia, including reduced educational attainment and increased socioemotional difficulties. The strongest pre-literacy predictors of dyslexia are rapid automatized naming (RAN), phonological awareness (PA), letter knowledge, and verbal short-term memory. The relationship among these constructs has been debated, and several theories have emerged to explain the unique role of each in reading ability/disability. Furthermore, the stability of identification of risk based on these measures varies widely across studies, due in part to the different cut-offs employed to designate risk. We applied a latent profile analysis technique with a diverse sample of 1215 kindergarten and pre-kindergarten students from 20 schools, to investigate whether PA, RAN, letter knowledge, and verbal short-term memory measures differentiated between homogenous profiles of performance on these measures. Six profiles of performance emerged from the data: average performers, below average performers, high performers, PA risk, RAN risk, and double-deficit risk (both PA and RAN). A latent class regression model was employed to investigate the longitudinal stability of these groups in a representative subset of children (n = 95) nearly two years later, at the end of 1st grade. Profile membership in the spring semester of pre-kindergarten or fall semester of kindergarten was significantly predictive of later reading performance, with the specific patterns of performance on the different constructs remaining stable across the years. There was a higher frequency of PA and RAN deficits in children from lower socioeconomic status (SES) backgrounds. There was no evidence for the IQ–achievement discrepancy criterion traditionally used to diagnose dyslexia. Our results support the feasibility of early identification of dyslexia risk and point to the heterogeneity of risk profiles. Thes

Neuroscience research has elucidated broad relationships between socioeconomic status (SES) and young children’s brain structure, but there is little mechanistic knowledge about specific environmental factors that are associated with specific variation in brain structure. One environmental factor, early language exposure, predicts children’s linguistic and cognitive skills and later academic achievement, but how language exposure relates to neuroanatomy is unknown. By measuring the real-world language exposure of young children (ages 4 – 6 years, 27 male/13 female), we confirmed the preregistered hypothesis that greater adult-child conversational experience, independent of SES and the sheer amount of adult speech, is related to stronger, more coherent white matter connectivity in the left arcuate and superior longitudinal fasciculi on average, and specifically near their anterior termination at Broca’s area in left inferior frontal cortex. Fractional anisotropy of significant tract subregions mediated the relationship between conversational turns and children’s language skills and indicated a neuroanatomical mechanism underlying the SES “language gap.” Post hoc whole-brain analyses revealed that language exposure was not related to any other white matter tracts, indicating the specificity of this relationship. Results suggest that the development of dorsal language tracts is environmentally influenced, specifically by early, dialogic interaction. Furthermore, these findings raise the possibility that early intervention programs aiming to ameliorate disadvantages in development due to family SES may focus on increasing children’s conversational exposure to capitalize on the early neural plasticity underlying cognitive development., National Institute of Child Health and Human Development (Grant F31HD086957)

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety., National Institute of Mental Health (Grant U01MH108168), NAH (Grant F32MH114525), NAH (Grant F32MH114525, R01EB021265, U01EB026996, R37MH068376, R01MH101521, R01MH119771, R56MH121426, R01EB020740, P41EB019936, R01AT007257, and R01MH099021)

Reading is a learned skill crucial for educational attainment. Children from families of lower socioeconomic status (SES) tend to have poorer reading performance and this gap widens across years of schooling. Reading relies on the orchestration of multiple neural systems integrated via specific white-matter pathways, but there is limited understanding about whether these pathways relate differentially to reading performance depending on SES background. Kindergarten white-matter FA and second-grade reading outcomes were investigated in an SES-diverse sample of 125 children. The three left-hemisphere white-matter tracts most associated with reading, and their right-hemisphere homologs, were examined: arcuate fasciculus (AF), superior longitudinal fasciculus (SLF), and inferior longitudinal fasciculus (ILF). There was a significant and positive association between SES and fractional anisotropy (FA) in the bilateral ILF in kindergarten. SES moderated the association between kindergarten ILF and second grade reading performance, such that it was positive in lower-SES children, but not significant in higher-SES children. These results have implications for understanding the role of the environment in the development of the neural pathways that support reading., National Institutes of Health (Grant R01HD067312), National Institute of Child Health and Human Development (Grant R01HD067312)

Delineation of functional topography is critical to the evolving understanding of the cerebellum's role in a wide range of nervous system functions. We used data from the Human Connectome Project (n = 787) to analyze cerebellar fMRI task activation (motor, working memory, language, social and emotion processing) and resting-state functional connectivity calculated from cerebral cortical seeds corresponding to the peak Cohen's d of each task contrast. The combination of exceptional statistical power, activation from both motor and multiple non-motor tasks in the same participants, and convergent resting-state networks in the same participants revealed novel aspects of the functional topography of the human cerebellum. Consistent with prior studies there were two distinct representations of motor activation. Newly revealed were three distinct representations each for working memory, language, social, and emotional task processing that were largely separate for these four cognitive and affective domains. In most cases, the task-based activations and the corresponding resting-network correlations were congruent in identifying the two motor representations and the three non-motor representations that were unique to working memory, language, social cognition, and emotion. The definitive localization and characterization of distinct triple representations for cognition and emotion task processing in the cerebellum opens up new basic science questions as to why there are triple representations (what different functions are enabled by the different representations?) and new clinical questions (what are the differing consequences of lesions to the different representations?). Keywords: Task-based fMRI; Resting state fMRI; Cerebellar topography; Cognition; Sensorimotor

The subthalamic nucleus (STN) is a small structure situated deep in the midbrain that exhibits wide-ranging functionality. In addition to its role in motor control, the STN is considered a hub for synchronizing aspects of emotion and cognition including attention, inhibitory control, motivation, and working memory. Evidence from neuroanatomical tracer studies suggests that the medial, ventromedial, and dorsolateral parts of the STN correspond to limbic, associative, and motor subdivisions, respectively. Although the extent of STN functional anatomical overlap remains unclear, blood oxygenation level dependent imaging of the STN may provide complementary information about the diverse functions of this structure. Methodological limitations in spatial and temporal resolutions, however, have prevented a comprehensive exploration of temporal correlations from the STN to the whole brain. In this study, we optimize spatial (2 mm isotropic) and temporal (TR = 1 s) resolutions to take full advantage of the time series signal-to-noise ratio capabilities of multichannel array coils and simultaneous multislice imaging. We interrogated STN seed-to-voxel resting-state functional MRI connectivity in a group of 30 healthy participants that included the whole brain at high-temporal and spatial resolutions. This analysis revealed STN functional connectivity to limbic, associative, and motor networks. Our findings contribute to the understanding of STN functional neuroanatomy in humans and are clinically relevant for ongoing research in deep brain stimulation.

Early life stress has been associated with disrupted functional connectivity between the amygdala and medial prefrontal cortex (mPFC), but it is unknown how early in development stress-related differences in amygdala-mPFC connectivity emerge. In a resting-state functional connectivity (rs-FC) analysis with 79 four- to seven-year-old children, we found a significant correlation between more adverse experiences and weaker amygdala-mPFC rs-FC. We also found that weaker amygdala-mPFC rs-FC was associated with higher levels of aggressive behavior and attention problems. These findings suggest that the impact of stress on emotional circuitry is detectable in early childhood and that this impact is associated with mental health difficulties. Connectivity in this circuit may be useful as a marker for mental health risk and for tracking the efficacy of early interventions.

Although lower socioeconomic status (SES) is generally negatively associated with performance on cognitive assessments, some children from lower-SES backgrounds perform as well as their peers from higher-SES backgrounds. Yet little research has examined whether the neural correlates of individual differences in cognition vary by SES. The current study explored whether relationships between cortical structure and fluid reasoning differ by SES in development. Fluid reasoning, a non-verbal component of IQ, is supported by a distributed frontoparietal network, with evidence for a specific role of rostrolateral prefrontal cortex (RLPFC). In a sample of 115 4–7-year old children, bilateral thickness of RLPFC differentially related to reasoning by SES: thicker bilateral RLPFC positively correlated with reasoning ability in children from lower-SES backgrounds, but not in children from higher-SES backgrounds. Similar results were found in an independent sample of 59 12–16-year old adolescents. Furthermore, young children from lower-SES backgrounds with strong reasoning skills were the only group to show a positive relationship between RLPFC thickness and age. In sum, we found that relationships between cortical thickness and cognition differ by SES during development.

Although numerous survey studies have reported connections between sleep and cognitive function, there remains a lack of quantitative data using objective measures to directly assess the association between sleep and academic performance. In this study, wearable activity trackers were distributed to 100 students in an introductory college chemistry class (88 of whom completed the study), allowing for multiple sleep measures to be correlated with in-class performance on quizzes and midterm examinations. Overall, better quality, longer duration, and greater consistency of sleep correlated with better grades. However, there was no relation between sleep measures on the single night before a test and test performance; instead, sleep duration and quality for the month and the week before a test correlated with better grades. Sleep measures accounted for nearly 25% of the variance in academic performance. These findings provide quantitative, objective evidence that better quality, longer duration, and greater consistency of sleep are strongly associated with better academic performance in college. Gender differences are discussed.

Dyslexia is a common neurobiological disorder in which a child fails to acquire typical word reading skills despite adequate opportunity and intelligence. The visual word form area (VWFA) is a region within the left fusiform gyrus that specializes for print over the course of reading acquisition and is often hypoactivated in individuals with dyslexia. It is currently unknown whether atypicalities in this brain region are already present in kindergarten children who will subsequently develop dyslexia. Here, we measured fMRI activation in response to letters and false fonts in bilateral fusiform gyrus in children with and without risk for dyslexia (defined by family history or low scores on assessments of pre-reading skills, such as phonological awareness). We then followed these children longitudinally through the end of second grade to evaluate whether brain activation patterns in kindergarten were related to second-grade reading outcomes. Compared to typical readers who exhibited no risk factors for reading impairment in kindergarten, there was significant hypoactivation to both letters and false-fonts in the left fusiform gyrus in at-risk children who subsequently developed reading impairment, but not in at-risk children who developed typical reading skills. There were no significant differences in letter- or false-font responses in the right fusiform gyrus among the groups. The finding that hypoactivation to print in the VWFA is present in children who subsequently develop reading impairment even prior to the onset of formal reading instruction suggests that atypical responses to print play an early role in the development of reading impairments such as dyslexia., NIH/NICHD (Award R01HD067312)

Individuals with Autism Spectrum Disorders (ASD) report difficulties extracting meaningful information from dynamic and complex social cues, like facial expressions. The nature and mechanisms of these difficulties remain unclear. Here we tested whether that difficulty can be traced to the pattern of activity in “social brain” regions, when viewing dynamic facial expressions. In two studies, adult participants (male and female) watched brief videos of a range of positive and negative facial expressions, while undergoing functional magnetic resonance imaging (Study 1: ASD n = 16, control n = 21; Study 2: ASD n = 22, control n = 30). Patterns of hemodynamic activity differentiated among facial emotional expressions in left and right superior temporal sulcus, fusiform gyrus, and parts of medial prefrontal cortex. In both control participants and high-functioning individuals with ASD, we observed (i) similar responses to emotional valence that generalized across facial expressions and animated social events; (ii) similar flexibility of responses to emotional valence, when manipulating the task-relevance of perceived emotions; and (iii) similar responses to a range of emotions within valence. Altogether, the data indicate that there was little or no group difference in cortical responses to isolated dynamic emotional facial expressions, as measured with fMRI. Difficulties with real-world social communication and social interaction in ASD may instead reflect differences in initiating and maintaining contingent interactions, or in integrating social information over time or context.

Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia. Keywords: KIAA0319; gene; reading; neural variability; subgroups; mechanisms, MGH Institute of Health Professions, Halis Foundation for Dyslexia Research

Although research highlights neural correlates of Major Depressive Disorder (MDD), it is unclear whether these correlates reflect the state of depression or a pre-existing risk factor. The current study examined whether baseline differences in brain activations, resting-state connectivity, and brain structural differences between non-symptomatic children at high- and low-risk for MDD based on familial depression prospectively predict the onset of a depressive episode or increases in depressive symptomatology. We re-assessed 44 participants (28 high-risk; 16 low-risk) who had undergone neuroimaging in a previous study 3–4 years earlier (Mean age at follow-up = 14.3 years, SD = 1.9 years; 45% females; 70% Caucasian). We investigated whether baseline brain imaging data (including an emotional face match task fMRI, resting-state fMRI and structural MRI) that differentiated the risk groups also predicted the onset of depression. Resting-state functional connectivity abnormalities in the default mode and cognitive control network that differentiated high-risk from low-risk youth at baseline predicted the onset of MDD during adolescence, after taking risk status into account. Increased functional activation to both happy and fearful faces was associated with greater decreases in self-reported depression symptoms at follow-up. This preliminary evidence could be used to identify youth at-risk for depression and inform early intervention strategies. ©2019