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1.  Developmental imaging genetics: linking dopamine function to adolescent behavior 
Brain and cognition  2013;89:27-38.
Adolescence is a period of development characterized by numerous neurobiological changes that significantly influence behavior and brain function. Adolescence is of particular interest due to the alarming statistics indicating that mortality rates increase two to three-fold during this time compared to childhood, due largely to a peak in risk-taking behaviors resulting from increased impulsivity and sensation seeking. Furthermore, there exists large unexplained variability in these behaviors that are in part mediated by biological factors. Recent advances in molecular genetics and functional neuroimaging have provided a unique and exciting opportunity to noninvasively study the influence of genetic factors on brain function in humans. While genes do not code for specific behaviors, they do determine the structure and function of proteins that are essential to the neuronal processes that underlie behavior. Therefore, studying the interaction of genotype with measures of brain function over development could shed light on critical time points when biologically mediated individual differences in complex behaviors emerge. Here we review animal and human literature examining the neurobiological basis of adolescent development related to dopamine neurotransmission. Dopamine is of critical importance because of (1) its role in cognitive and affective behaviors, (2) its role in the pathogenesis of major psychopathology, and (3) the protracted development of dopamine signaling pathways over adolescence. We will then focus on current research examining the role of dopamine-related genes on brain function. We propose the use of imaging genetics to examine the influence of genetically mediated dopamine variability on brain function during adolescence, keeping in mind the limitations of this approach.
PMCID: PMC4226044  PMID: 24139694
2.  Developmental Stages and Sex Differences of White Matter and Behavioral Development through Adolescence: A Longitudinal Diffusion Tensor Imaging (DTI) Study 
NeuroImage  2013;92:356-368.
White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals ages 8-28, who received annual scans for up to 5 years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical-subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition-emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.
PMCID: PMC4301413  PMID: 24384150
maturation; uncinate fasciculus; cingulum; prefrontal; inhibition; variability
3.  Circuitry underlying temporally extended spatial working memory 
NeuroImage  2006;35(2):904-915.
Extended maintenance delays decrease the accuracy of information stored in spatial working memory. In order to elucidate the network underlying sustained spatial working memory, 16 subjects were scanned using fast event-related fMRI as they performed an oculomotor delayed response task containing trials with “short” (2.5 s) or “long” (10 s) delay periods. Multiple cortical and subcortical regions were common to both delay trial types indicating core task regions. Three patterns of activity were found in a subset of core regions that reflect underlying processes: maintenance-related (e.g., left FEF, right supramarginal gyrus (SMG)), response planning-related (e.g., right FEF, SEF), and motor response-related (e.g., lateral cerebellum (declive)) activation. Several regions were more active during long than short delay trials, including multiple sites in DLPFC (BA 9, 46), indicating a circuitry dynamically recruited to support sustained working memory. Our results suggest that specialized brain processes support extended periods of working memory.
PMCID: PMC4397654  PMID: 17292627
fMRI; Oculomotor; Working memory; Maintenance; Cognition; DLPFC; FEF
4.  Cortical Neurodynamics of Inhibitory Control 
The Journal of Neuroscience  2014;34(29):9551-9561.
The ability to inhibit prepotent responses is critical for successful goal-directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18–38 Hz) in the lateral PFC and alpha-band power (10–18 Hz) in the frontal eye field (FEF) increased. Trial-by-trial prestimulus FEF alpha-band power predicted successful saccadic inhibition. Further, inhibitory control enhanced cross-frequency amplitude coupling between PFC beta-band (18–38 Hz) activity and FEF alpha-band activity, and the coupling appeared to be initiated by the PFC. Our results suggest a generalized mechanism for top-down inhibitory control: prefrontal beta-band activity initiates alpha-band activity for functional inhibition of the effector and/or sensory system.
PMCID: PMC4099539  PMID: 25031398
antisaccade; inhibitory control; neural oscillations; prefrontal cortex
5.  fNIRS Evidence of Prefrontal Regulation of Frustration in Early Childhood 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.04.057.
The experience of frustration is common in early childhood, yet some children seem to possess a lower tolerance for frustration than others. Characterizing the biological mechanisms underlying a wide range of frustration tolerance observed in early childhood may inform maladaptive behavior and psychopathology that is associated with this construct. The goal of this study was to measure prefrontal correlates of frustration in 3–5 year-old children, who are not readily adaptable for typical neuroimaging approaches, using functional near infrared spectroscopy (fNIRS). fNIRS of frontal regions were measured as frustration was induced in children through a computer game where a desired and expected prize was “stolen” by an animated dog. A fNIRS general linear model (GLM) was used to quantify the correlation of brain regions with the task and identify areas that were statistically different between the winning and frustrating test conditions. A second-level voxel-based ANOVA analysis was then used to correlate the amplitude of each individual’s brain activation with measure of parent-reported frustration. Experimental results indicated increased activity in the middle prefrontal cortex during winning of a desired prize, while lateral prefrontal cortex activity increased during frustration. Further, activity increase in lateral prefrontal cortex during frustration correlated positively with parent-reported frustration tolerance. These findings point to the role of the lateral prefrontal cortex as a potential region supporting the regulation of emotion during frustration.
PMCID: PMC3796135  PMID: 23624495
Frustration; Emotion Regulation; fNIRS; Development; Early Childhood; Prefrontal Cortex
6.  Cognitive Control and Motivation 
Adolescence is associated with heightened mortality rates due in large measure to negative consequences from risky behaviors. Theories of adolescent risk taking posit that immature cognitive control coupled with heightened reward reactivity drive adolescent risk-taking, yet surprisingly few empirical studies have examined these neurobiological systems together. In this paper, we describe a related series of studies from our laboratory aimed at further delineating the maturation of cognitive control through adolescence, as well as how rewards influence a key aspect of cognitive control, response inhibition. Our findings indicate that adolescents can exert adult-like control over their behavior, but that they have limitations regarding the consistency with which they can generate optimal responses compared to adults. Moreover, we demonstrate that the brain circuitry supporting mature cognitive (inhibitory) control is still undergoing development. Our work using the rewarded antisaccade task, a paradigm that enables concurrent assessment of rewards and inhibitory control, indicates that adolescents show delayed but heightened responses in key reward regions along with concurrent activation in brain systems that support behaviors leading to reward acquisition. Considered together, our results highlight adolescent-specific differences in the integration of basic brain processes that may underlie decision-making and more complex risk taking in adolescence.
PMCID: PMC4285389  PMID: 25574074
prefrontal; antisaccade; inhibition; dopamine; oculomotor
7.  An open science resource for establishing reliability and reproducibility in functional connectomics 
Zuo, Xi-Nian | Anderson, Jeffrey S | Bellec, Pierre | Birn, Rasmus M | Biswal, Bharat B | Blautzik, Janusch | Breitner, John C.S | Buckner, Randy L | Calhoun, Vince D | Castellanos, F. Xavier | Chen, Antao | Chen, Bing | Chen, Jiangtao | Chen, Xu | Colcombe, Stanley J | Courtney, William | Craddock, R Cameron | Di Martino, Adriana | Dong, Hao-Ming | Fu, Xiaolan | Gong, Qiyong | Gorgolewski, Krzysztof J | Han, Ying | He, Ye | He, Yong | Ho, Erica | Holmes, Avram | Hou, Xiao-Hui | Huckins, Jeremy | Jiang, Tianzi | Jiang, Yi | Kelley, William | Kelly, Clare | King, Margaret | LaConte, Stephen M | Lainhart, Janet E | Lei, Xu | Li, Hui-Jie | Li, Kaiming | Li, Kuncheng | Lin, Qixiang | Liu, Dongqiang | Liu, Jia | Liu, Xun | Liu, Yijun | Lu, Guangming | Lu, Jie | Luna, Beatriz | Luo, Jing | Lurie, Daniel | Mao, Ying | Margulies, Daniel S | Mayer, Andrew R | Meindl, Thomas | Meyerand, Mary E | Nan, Weizhi | Nielsen, Jared A | O’Connor, David | Paulsen, David | Prabhakaran, Vivek | Qi, Zhigang | Qiu, Jiang | Shao, Chunhong | Shehzad, Zarrar | Tang, Weijun | Villringer, Arno | Wang, Huiling | Wang, Kai | Wei, Dongtao | Wei, Gao-Xia | Weng, Xu-Chu | Wu, Xuehai | Xu, Ting | Yang, Ning | Yang, Zhi | Zang, Yu-Feng | Zhang, Lei | Zhang, Qinglin | Zhang, Zhe | Zhang, Zhiqiang | Zhao, Ke | Zhen, Zonglei | Zhou, Yuan | Zhu, Xing-Ting | Milham, Michael P
Scientific Data  2014;1:140049.
Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.
PMCID: PMC4421932  PMID: 25977800
8.  The Autism Brain Imaging Data Exchange: Towards Large-Scale Evaluation of the Intrinsic Brain Architecture in Autism 
Molecular psychiatry  2013;19(6):659-667.
Autism spectrum disorders (ASD) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, life-long nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. While the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE) – a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) datasets with corresponding structural MRI and phenotypic information from 539 individuals with ASD and 573 age-matched typical controls (TC; 7–64 years) ( Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 males with ASD and 403 male age-matched TC. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo and hyperconnectivity in the ASD literature; both were detected, though hypoconnectivity dominated, particularly for cortico-cortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASD (mid and posterior insula, posterior cingulate cortex), and highlighted less commonly explored regions such as thalamus. The survey of the ABIDE R-fMRI datasets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international datasets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
PMCID: PMC4162310  PMID: 23774715
Resting state fMRI; Intrinsic functional connectivity; Data sharing; Large-scale networks; Default network; Interhemispheric connectivity; Thalamus
9.  The Nuisance of Nuisance Regression: Spectral Misspecification in a Common Approach to Resting-State fMRI Preprocessing Reintroduces Noise and Obscures Functional Connectivity 
NeuroImage  2013;0:208-225.
Recent resting-state functional connectivity fMRI (RS-fcMRI) research has demonstrated that head motion during fMRI acquisition systematically influences connectivity estimates despite bandpass filtering and nuisance regression, which are intended to reduce such nuisance variability. We provide evidence that the effects of head motion and other nuisance signals are poorly controlled when the fMRI time series are bandpass-filtered but the regressors are unfiltered, resulting in the inadvertent reintroduction of nuisance-related variation into frequencies previously suppressed by the bandpass filter, as well as suboptimal correction for noise signals in the frequencies of interest. This is important because many RS-fcMRI studies, including some focusing on motion-related artifacts, have applied this approach. In two cohorts of individuals (n = 117 and 22) who completed resting-state fMRI scans, we found that the bandpass-regress approach consistently overestimated functional connectivity across the brain, typically on the order of r = .10 – .35, relative to a simultaneous bandpass filtering and nuisance regression approach. Inflated correlations under the bandpass-regress approach were associated with head motion and cardiac artifacts. Furthermore, distance-related differences in the association of head motion and connectivity estimates were much weaker for the simultaneous filtering approach. We recommend that future RS-fcMRI studies ensure that the frequencies of nuisance regressors and fMRI data match prior to nuisance regression, and we advocate a simultaneous bandpass filtering and nuisance regression strategy that better controls nuisance-related variability.
PMCID: PMC3759585  PMID: 23747457
Resting-state fMRI; bandpass filtering; nuisance regression; artifacts; preprocessing
10.  The Development of Hub Architecture in the Human Functional Brain Network 
Cerebral Cortex (New York, NY)  2012;23(10):2380-2393.
Functional hubs are brain regions that play a crucial role in facilitating communication among parallel, distributed brain networks. The developmental emergence and stability of hubs, however, is not well understood. The current study used measures of network topology drawn from graph theory to investigate the development of functional hubs in 99 participants, 10–20 years of age. We found that hub architecture was evident in late childhood and was stable from adolescence to early adulthood. Connectivity between hub and non-hub (“spoke”) regions, however, changed with development. From childhood to adolescence, the strength of connections between frontal hubs and cortical and subcortical spoke regions increased. From adolescence to adulthood, hub–spoke connections with frontal hubs were stable, whereas connectivity between cerebellar hubs and cortical spoke regions increased. Our findings suggest that a developmentally stable functional hub architecture provides the foundation of information flow in the brain, whereas connections between hubs and spokes continue to develop, possibly supporting mature cognitive function.
PMCID: PMC3767958  PMID: 22875861
adolescents; brain networks; development; functional connectivity; graph theory
11.  Inhibitory Control and Working Memory in Post-Institutionalized Children 
Inhibitory control and working memory were examined in post-institutionalized (PI) children adopted into United States families from Russian institutions. The PI sample originated from institutions that were less severely depriving than those represented in previous studies and approximated the level of psychosocial deprivation, which is characterized by adequate physical resources but a lack of consistent and responsive caregiving. PI children (N=75; 29 male) ranged in age from 8–17 years (M=12.97; SD=3.03) and were grouped according to whether they were adopted after 14 months or before 9 months. A non-adopted comparison group (N=133; 65 male) ranged in age from 8–17 years (M=12.26; SD=2.75). PI children adopted after 14 months of age displayed poorer performance on the stop-signal and spatial span tasks relative to PI children adopted before 9 months of age after controlling for age at assessment. The two PI groups did not differ in their performance on a spatial self-ordered search task. Older-adopted PI children also showed poorer spatial span task performance compared to non-adopted children, but younger-adopted PI children did not. Task performance was significantly associated with parent-rated hyperactive-impulsive behavior in everyday contexts. These findings suggest that exposure to prolonged early institutional deprivation may be linked with inhibitory control and working memory difficulties years after adoption.
PMCID: PMC3708995  PMID: 23519375
early deprivation; post-institutionalized children; inhibitory control; working memory
12.  Longitudinal Growth Curves of Brain Function Underlying Inhibitory Control through Adolescence 
The Journal of Neuroscience  2013;33(46):18109-18124.
Neuroimaging studies suggest that developmental improvements in inhibitory control are primarily supported by changes in prefrontal executive function. However, studies are contradictory with respect to how activation in prefrontal regions changes with age, and they have yet to analyze longitudinal data using growth curve modeling, which allows characterization of dynamic processes of developmental change, individual differences in growth trajectories, and variables that predict any interindividual variability in trajectories. In this study, we present growth curves modeled from longitudinal fMRI data collected over 302 visits (across ages 9 to 26 years) from 123 human participants. Brain regions within circuits known to support motor response control, executive control, and error processing (i.e., aspects of inhibitory control) were investigated. Findings revealed distinct developmental trajectories for regions within each circuit and indicated that a hierarchical pattern of maturation of brain activation supports the gradual emergence of adult-like inhibitory control. Mean growth curves of activation in motor response control regions revealed no changes with age, although interindividual variability decreased with development, indicating equifinality with maturity. Activation in certain executive control regions decreased with age until adolescence, and variability was stable across development. Error-processing activation in the dorsal anterior cingulate cortex showed continued increases into adulthood and no significant interindividual variability across development, and was uniquely associated with task performance. These findings provide evidence that continued maturation of error-processing abilities supports the protracted development of inhibitory control over adolescence, while motor response control regions provide early-maturing foundational capacities and suggest that some executive control regions may buttress immature networks as error processing continues to mature.
PMCID: PMC3828464  PMID: 24227721
13.  The development of individuation in autism 
Evidence suggests that people with autism use holistic information differently than typical adults. The current studies examine this possibility by investigating how core visual processes that contribute to holistic processing – individuation and element grouping – develop in participants with autism and typically developing (TD) participants matched for age, IQ and gender. Individuation refers to the ability to `see' up to 4 elements simultaneously; grouping these elements can change the number of elements that are rapidly apprehended. We examined these core processes using two well-established paradigms, rapid enumeration and multiple object tracking (MOT). In both tasks, a performance limit of about 4 elements in adulthood is thought to reflect individuation capacity. Participants with autism has a smaller individuation capacity than TD controls, regardless of whether they were enumerating static elements or tracking moving ones. To manipulate holistic information and individuation performance, we grouped the elements into a design or had elements move together. Participants with autism were affected to a similar degree as TD participants by the holistic information, whether the manipulation helped or hurt performance, consistent with evidence that some types of gestalt/grouping information are processed typically in autism. There was substantial development in autism from childhood to adolescence, but not from adolescence to adulthood, a pattern distinct from TD participants. These results provide important information about core visual processes in autism, as well as insight into the architecture of vision (e.g., individuation appears distinct from visual strengths in autism, such as visual search, despite similarities).
PMCID: PMC3608798  PMID: 22963232
autism; subitizing; global-local; individuation; holistic; configural; grouping; gestalt; indexing
14.  Oculomotor Assessments of Executive Function in Preterm Children 
The Journal of pediatrics  2012;161(3):427-433.e1.
To use objective, nonverbal oculomotor tasks to assess executive function and infer the neural basis of impairments in preterm children.
Study design
Cross-sectional study of preterm children age 9 to 16 years (n = 69; mean gestational age 29 weeks) and full term controls (n = 43). Tasks assessed sensorimotor function (reflexive prosaccades); resistance to peripheral distracters (fixation); response inhibition, response preparation, and execution of a voluntary saccade (antisaccades); and spatial working memory (memory-guided saccades). Group differences were analyzed using ANOVA. We used linear regression to analyze the contributions of age, sex, gestational age, and white matter category to task performance.
Preterm children did not differ from controls on basic sensorimotor function, response inhibition, and working memory. Compared with controls, preterm children showed greater susceptibility to peripheral distracters (p = .008) and were slower to initiate an inhibitory response (p = .003). Regression models showed contributions of age and white matter category to task performance.
Preterm children show intact basic sensorimotor function and demonstrate difficulties in processes underlying executive control, including increased distractibility and prolonged response preparation. These limitations may reflect specific neural abnormalities in fronto-subcortical executive control of behavior.
PMCID: PMC3638733  PMID: 22480696
preterm; premature birth; oculomotor; saccade; executive function; response inhibition; response preparation
15.  Sex differences in physiological reactivity to acute psychosocial stress in adolescence 
Psychoneuroendocrinology  2012;37(8):1135-1157.
Females begin to demonstrate greater negative affective responses to stress than males in adolescence. This may reflect the concurrent emergence of underlying differences in physiological response systems, including corticolimbic circuitries, the hypothalamic—pituitary— adrenal axis (HPAA), and the autonomic nervous system (ANS). This review examines when sex differences in physiological reactivity to acute psychosocial stress emerge and the directionality of these differences over development. Indeed, the literature indicates that sex differences emerge during adolescence and persist into adulthood for all three physiological response systems. However, the directionality of the differences varies by system. The emerging corti-colimbic reactivity literature suggests greater female reactivity, particularly in limbic regions densely innervated by gonadal hormone receptors. In contrast, males generally show higher levels of HPAA and ANS reactivity. We argue that the contrasting directionality of corticolimbic and peripheral physiological responses may reflect specific effects of gonadal hormones on distinct systems and also sex differences in evolved behavioral responses that demand different levels of peripheral physiological activation. Studies that examine both subjective reports of negative affect and physiological responses indicate that beginning in adolescence, females respond to acute stressors with more intense negative affect than males despite their comparatively lower peripheral physiological responses. This dissociation is not clearly explained by sex differences in the strength of the relationship between physiological and subjective responses. We suggest that females' greater subjective responsivity may instead arise from a greater activity in brain regions that translate stress responses to subjective awareness in adolescence. Future research directions include investigations of the role of pubertal hormones in physiological reactivity across all systems, examining the relationship of corticolimbic reactivity and negative affect, and sex differences in emotion regulation processes.
PMCID: PMC3472630  PMID: 22281210
Adolescent; Autonomic nervous system; Corticolimbic system; Hypothalamic—pituitary—adrenal axis; Sex differences; Psychosocial stress
16.  Developmental Effects of Incentives on Response Inhibition 
Child Development  2012;83(4):1262-1274.
Inhibitory control and incentive processes underlie decision-making, yet few studies have explicitly examined their interaction across development. Here, the effects of potential rewards and losses on inhibitory control in sixty-four adolescents (13-17-year-olds) and forty-two young adults (18-29-year-olds) were examined using an incentivized antisaccade task. Notably, measures were implemented to minimize age-related differences in reward valuation and potentially confounding motivation effects. Incentives affected antisaccade metrics differently across the age groups. Younger adolescents generated more errors than adults on reward trials, but all groups performed well on loss trials. Adolescent saccade latencies also differed from adults across the range of reward trials. Overall, results suggest persistent immaturities in the integration of reward and inhibitory control processes across adolescence.
PMCID: PMC3399954  PMID: 22540668
17.  White matter microstructure on diffusion tensor imaging is associated with conventional magnetic resonance imaging findings and cognitive function in adolescents born preterm 
Diffusion tensor imaging (DTI) was used to evaluate white matter architecture after preterm birth. The goals were (1) to compare white matter microstructure in two cohorts of preterm- and term-born children; and (2) within preterm groups, to determine if sex, gestational age, birthweight, white matter injury score from conventional magnetic resonance imaging (MRI), or IQ was associated with DTI measures.
Participants (n=121; 66 females, 55 males) were aged 9 to 16 years. They comprised 58 preterm children (site 1, n=25; and site 2, n=33) born at less than 36 weeks’ gestation (mean 29.4wks; birthweight 1289g) and 63 term children (site 1, n=40; site 2, n=23) born at more than 37 weeks’ gestation. DTI was analyzed using tract-based spatial statistics. Diffusion measures were fractional anisotropy, axial, radial, and mean diffusivity.
In no region of the white matter skeleton was fractional anisotropy lower in the preterm group at either site. Within the preterm groups, fractional anisotropy was significantly associated with white matter injury score, but not sex, gestational age, or birthweight. At site 1, fractional anisotropy was associated with IQ.
DTI contributes to understanding individual differences after preterm birth but may not differentiate a relatively high-functioning group of preterm children from a matched group of term-born children.
PMCID: PMC3683593  PMID: 22803787
18.  Executive Function Skills are Associated with Reading and Parent-Rated Child Function in Children Born Prematurely 
Early human development  2011;88(2):111-118.
Preterm children are at risk for executive function (EF) problems, which have been linked to behavior and learning problems in full term children. In this study, we examine the relationship between EF and functional outcomes in preterm children.
To evaluate (1) EF skills of 9- to 16-year-old children born across the spectrum of gestational age (GA), (2) relationship of degree of prematurity to EF skills, and (3) contributions of EF skills to two functional outcomes--reading scores and parent-rated child function.
Preterm children <36 weeks gestation (n=72) were compared to full term children (n=42) of similar age, gender and SES, on measures of EF, reading, and parent-ratings of child function. Multiple regression models evaluated contributions to EF skills and functional outcomes.
Compared to full term controls, preterm children had poorer EF performance on a complex planning and organization task and did not increase planning time as task difficulty increased. Their spatial memory capacity was not different. GA contributed to EF skills, but was mediated by IQ. EF contributed to the variance in reading skills but did not add to the variance in reading when IQ was considered. EF skills significantly contributed to the variance in parent-rated child function, but IQ did not.
EF skills contribute to measures of functional outcome in this high-risk population. The use of EF skills as an early marker for learning and functional problems and as a target for intervention in children born preterm warrants future study.
PMCID: PMC3660611  PMID: 21849240
preterm birth; prematurity; executive function; CANTAB; reading; function
19.  Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD) 
PLoS ONE  2013;8(5):e63709.
The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.
PMCID: PMC3660571  PMID: 23704934
20.  Age related changes in striatal resting state functional connectivity in autism 
Characterizing the nature of developmental change is critical to understanding the mechanisms that are impaired in complex neurodevelopment disorders such as autism spectrum disorder (ASD) and, pragmatically, may allow us to pinpoint periods of plasticity when interventions are particularly useful. Although aberrant brain development has long been theorized as a characteristic feature of ASD, the neural substrates have been difficult to characterize, in part due to a lack of developmental data and to performance confounds. To address these issues, we examined the development of intrinsic functional connectivity, with resting state fMRI from late childhood to early adulthood (8–36 years), using a seed based functional connectivity method with the striatal regions. Overall, we found that both groups show decreases in cortico-striatal circuits over age. However, when controlling for age, ASD participants showed increased connectivity with parietal cortex and decreased connectivity with prefrontal cortex relative to typically developed (TD) participants. In addition, ASD participants showed aberrant age-related connectivity with anterior aspects of cerebellum, and posterior temporal regions (e.g., fusiform gyrus, inferior and superior temporal gyri). In sum, we found prominent differences in the development of striatal connectivity in ASD, most notably, atypical development of connectivity in striatal networks that may underlie cognitive and social reward processing. Our findings highlight the need to identify the biological mechanisms of perturbations in brain reorganization over development, which may also help clarify discrepant findings in the literature.
PMCID: PMC3842522  PMID: 24348363
autism; fMRI; resting state; functional connectivity; striatum; development
21.  Developmental changes in brain function underlying the influence of reward processing on inhibitory control 
Adolescence is a period marked by changes in motivational and cognitive brain systems. However, the development of the interactions between reward and cognitive control processing are just beginning to be understood. Using event-related functional neuroimaging and an incentive modulated antisaccade task, we compared blood-oxygen level dependent activity underlying motivated response inhibition in children, adolescents, and adults. Behaviorally, children and adolescents performed significantly worse than adults during neutral trials. However, children and adolescents showed significant performance increases during reward trials. Adults showed no performance changes across conditions. fMRI results demonstrated that all groups recruited a similar circuitry to support task performance, including regions typically associated with rewards (striatum and orbital frontal cortex), and regions known to be involved in inhibitory control (putative frontal and supplementary eye fields, and posterior parietal cortex, and prefrontal loci). During rewarded trials adolescents showed increased activity in striatal regions, while adults demonstrated heightened activation in the OFC relative to children and adolescents. Children showed greater reliance on prefrontal executive regions that may be related to increased effort inhibiting responses. Overall, these results indicate that response inhibition is enhanced with reward contingencies over development. Adolescents’ heightened response in striatal regions may be one factor contributing to reward-biased decision making and perhaps risk taking behavior.
PMCID: PMC3181104  PMID: 21966352
adolescence; reward; inhibitory control; antisaccade; fMRI
22.  “What” Precedes “Which”: Developmental Neural Tuning in Face- and Place-Related Cortex 
Cerebral Cortex (New York, NY)  2011;21(9):1963-1980.
Although category-specific activation for faces in the ventral visual pathway appears adult-like in adolescence, recognition abilities for individual faces are still immature. We investigated how the ability to represent “individual” faces and houses develops at the neural level. Category-selective regions of interest (ROIs) for faces in the fusiform gyrus (FG) and for places in the parahippocampal place area (PPA) were identified individually in children, adolescents, and adults. Then, using an functional magnetic resonance imaging adaptation paradigm, we measured category selectivity and individual-level adaptation for faces and houses in each ROI. Only adults exhibited both category selectivity and individual-level adaptation bilaterally for faces in the FG and for houses in the PPA. Adolescents showed category selectivity bilaterally for faces in the FG and houses in the PPA. Despite this profile of category selectivity, adolescents only exhibited individual-level adaptation for houses bilaterally in the PPA and for faces in the “left” FG. Children only showed category-selective responses for houses in the PPA, and they failed to exhibit category-selective responses for faces in the FG and individual-level adaptation effects anywhere in the brain. These results indicate that category-level neural tuning develops prior to individual-level neural tuning and that face-related cortex is disproportionately slower in this developmental transition than is place-related cortex.
PMCID: PMC3202723  PMID: 21257673
adolescent; fMRI; fusiform gyrus; parahippocampal gyrus; visual processing
23.  Enhancing response inhibition by incentive: Comparison of adolescents with and without substance use disorder 
Drug and alcohol dependence  2010;115(1-2):43-50.
Effective response inhibition is a key component of recovery from addiction. Some research suggests that response inhibition can be enhanced through reward contingencies. We examined the effect of monetary incentive on response inhibition among adolescents with and without substance use disorder (SUD) using a fast event-related fMRI antisaccade reward task. The fMRI task permits investigation of how reward (monetary incentive) might modulate inhibitory control during three task phases: cue presentation (reward or neutral trial), response preparation, and response execution. Adolescents with lifetime SUD (n=12; 100% marijuana use disorder) were gender and age-matched to healthy controls (n=12). Monetary incentive facilitated inhibitory control for SUD adolescents; for healthy controls, the difference in error rate for neutral and reward trials was not significant. There were no significant differences in behavioral performance between groups across reward and neutral trials, however, group differences in regional brain activation were identified. During the response preparation phase of reward trials, SUD adolescents, compared to controls, showed increased activation of prefrontal and oculomotor control (e.g., frontal eye field) areas, brain regions that have been associated with effective response inhibition. Results indicate differences in brain activation between SUD and control youth when preparing to inhibit a prepotent response in the context of reward, and support a possible role for incentives in enhancing response inhibition among youth with SUD.
PMCID: PMC3047601  PMID: 21115229
adolescent; substance use disorder; fMRI; response inhibition; incentive; antisaccade
24.  Object recognition in Williams syndrome: Uneven ventral stream activation 
Developmental science  2010;14(3):549-565.
Williams syndrome (WS) is a genetic disorder associated with severe visuospatial deficits, relatively strong language skills, heightened social interest, and increased attention to faces. On the basis of the visuospatial impairments, this disorder has been characterized primarily as a deficit of the dorsal stream, the occipitoparietal brain regions that subserve visuospatial processing. However, some evidence indicates that this disorder may also affect the development of the ventral stream, the occipitotemporal cortical regions that subserve face and object recognition. The present studies examined ventral stream function in WS, with the hypothesis that faces would produce a relatively more mature pattern of ventral occipitotemporal cortical activation, relative to other objects that are also represented across these visual areas. We compared functional magnetic resonance imaging activation patterns during viewing of human faces, cat faces, houses and shoes in individuals with WS (age 14–27), typically developing 6–9 year olds (matched approximately on mental age), and typically developing 14–26 year olds (matched on chronological age). Typically developing individuals exhibited changes in the pattern of activation over age, consistent with previous reports. The ventral stream topography of the WS individuals differed from both control groups, however, reflecting the same level of activation to face stimuli as chronological age matches, but less activation to house stimuli than either mental age or chronological age matches. We discuss the possible causes of this unusual topography and implications for understanding the behavioral profile of people with WS.
PMCID: PMC3074094  PMID: 21477194
Williams syndrome; fMRI; ventral stream; FFA; face; temporal lobe; object recognition; mental retardation; intellectual disability; development; children
25.  Deficits in adults with Autism Spectrum Disorders when processing multiple objects in dynamic scenes 
Scientific Abstract
People with autism spectrum disorder (ASD) process visual information in a manner that is distinct from typically developing individuals. They may be less sensitive to people's goals and, more generally, focus on visual details instead of the entire scene. To examine these differences, people with and without ASD were asked to detect changes in dynamic scenes with multiple elements. Participants viewed a brief video of a person or an inanimate object moving from one object to another; after a delay, they reported whether a second video was the same or different. Possible changes included the figure, the object the figure was moving from, or the object it was moving toward (the ‘goal’). We hypothesized that individuals with ASD would be less sensitive to changes in scenes with people, particularly elements that might be the person's goal. Alternately, people with ASD might attend to fewer elements regardless of whether the scene included a person. Our results indicate that, like controls, people with ASD noticed a change in the ‘goal’ object at the end of a person's movement more often than the object at the start. However, the group with ASD did not undergo the developmental improvement when detecting changes in start and end objects that was evident typically. This led to deficits in adults with ASD that were not specific to scenes with people or to ‘goals’. Improvements in visual processing that underlie mature representation of scenes may not occur in ASD, suggesting late developing brain processes are affected.
PMCID: PMC3074038  PMID: 21254449
ASD; change detection; development; developmental disorder; people perception; social cognition

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