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1.  Fronto-parietal hypo-activation during working memory independent of structural abnormalities: Conjoint fMRI and sMRI analyses in adolescent offspring of schizophrenia patients 
NeuroImage  2011;58(1):234-241.
Adolescent offspring of schizophrenia patients (HR-S) are an important group in whom to study impaired brain function and structure, particularly of the frontal cortices. Studies of working memory have suggested behavioral deficits and fMRI-measured hypoactivity in fronto-parietal regions in these subjects. Independent structural MRI (sMRI) studies have suggested exaggerated frontal gray matter decline. Therefore the emergent view is that fronto-parietal deficits in function and structure characterize HR-S. However, it is unknown if fronto-parietal sub-regions in which fMRI-measured hypo-activity might be observed are precisely those regions of the cortex in which gray matter deficits are also observed. To investigate this question we conducted conjoint analyses of fronto-parietal function and structure in HR-S (n=19) and controls (n=24) with no family history of psychoses using fMRI data during a continuous working memory task (2 Back), and sMRI collected in the same session. HR-S demonstrated significantly reduced BOLD activation in left dorso-lateral prefrontal cortex (BA 9/46) and bilateral parietal cortex (BA 7/40). Sub-regions of interest were created from the significant fronto-parietal functional clusters. Analyses of gray matter volume from volume-modulated gray matter segments in these clusters did not reveal significant gray matter differences between groups. The results suggest that functional impairments in adolescent HR-S can be independent of impairments in structure, suggesting that the relationship between impaired function and structure is complex. Further studies will be needed to more closely assess whether impairments in function and structure provide independent or interacting pathways of vulnerability in this population.
doi:10.1016/j.neuroimage.2011.06.033
PMCID: PMC3164159  PMID: 21729757
Schizophrenia; Adolescent Offspring; Working Memory; Vulnerability; fMRI; Structural MRI
2.  Typical and Atypical Development of Functional Human Brain Networks: Insights from Resting-State fMRI 
Over the past several decades, structural MRI studies have provided remarkable insights into human brain development by revealing the trajectory of gray and white matter maturation from childhood to adolescence and adulthood. In parallel, functional MRI studies have demonstrated changes in brain activation patterns accompanying cognitive development. Despite these advances, studying the maturation of functional brain networks underlying brain development continues to present unique scientific and methodological challenges. Resting-state fMRI (rsfMRI) has emerged as a novel method for investigating the development of large-scale functional brain networks in infants and young children. We review existing rsfMRI developmental studies and discuss how this method has begun to make significant contributions to our understanding of maturing brain organization. In particular, rsfMRI has been used to complement studies in other modalities investigating the emergence of functional segregation and integration across short and long-range connections spanning the entire brain. We show that rsfMRI studies help to clarify and reveal important principles of functional brain development, including a shift from diffuse to focal activation patterns, and simultaneous pruning of local connectivity and strengthening of long-range connectivity with age. The insights gained from these studies also shed light on potentially disrupted functional networks underlying atypical cognitive development associated with neurodevelopmental disorders. We conclude by identifying critical gaps in the current literature, discussing methodological issues, and suggesting avenues for future research.
doi:10.3389/fnsys.2010.00021
PMCID: PMC2889680  PMID: 20577585
functional connectivity; brain maturation; resting-state fMRI; cognitive development; autism spectrum disorders; attention-deficit/hyperactivity disorder
3.  Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls 
Neuroimage  2011;57(4):1517-1523.
Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)—a key enzymatic regulator of cortical dopamine levels—to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val “dose” conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation.
doi:10.1016/j.neuroimage.2011.05.032
PMCID: PMC3285479  PMID: 21620981
Neuroimaging; COMT; Schizophrenia; Siblings; Cortex; Maturation; Dopamine
4.  The Development of Neural Synchrony and Large-Scale Cortical Networks During Adolescence: Relevance for the Pathophysiology of Schizophrenia and Neurodevelopmental Hypothesis 
Schizophrenia Bulletin  2011;37(3):514-523.
Recent data from developmental cognitive neuroscience highlight the profound changes in the organization and function of cortical networks during the transition from adolescence to adulthood. While previous studies have focused on the development of gray and white matter, recent evidence suggests that brain maturation during adolescence extends to fundamental changes in the properties of cortical circuits that in turn promote the precise temporal coding of neural activity. In the current article, we will highlight modifications in the amplitude and synchrony of neural oscillations during adolescence that may be crucial for the emergence of cognitive deficits and psychotic symptoms in schizophrenia. Specifically, we will suggest that schizophrenia is associated with impaired parameters of synchronous oscillations that undergo changes during late brain maturation, suggesting an important role of adolescent brain development for the understanding, treatment, and prevention of the disorder.
doi:10.1093/schbul/sbr034
PMCID: PMC3080681  PMID: 21505118
neural synchrony; adolescence; schizophrenia
5.  Human Parietal Cortex Structure Predicts Individual Differences in Perceptual Rivalry 
Current Biology  2010;20(18-4):1626-1630.
Summary
When visual input has conflicting interpretations, conscious perception can alternate spontaneously between competing interpretations [1]. There is a large amount of unexplained variability between individuals in the rate of such spontaneous alternations in perception [2–5]. We hypothesized that variability in perceptual rivalry might be reflected in individual differences in brain structure, because brain structure can exhibit systematic relationships with an individual's cognitive experiences and skills [6–9]. To test this notion, we examined in a large group of individuals how cortical thickness, local gray-matter density, and local white-matter integrity correlate with individuals' alternation rate for a bistable, rotating structure-from-motion stimulus [10]. All of these macroscopic measures of brain structure consistently revealed that the structure of bilateral superior parietal lobes (SPL) could account for interindividual variability in perceptual alternation rate. Furthermore, we examined whether the bilateral SPL regions play a causal role in the rate of perceptual alternations by using transcranial magnetic stimulation (TMS) and found that transient disruption of these areas indeed decreases the rate of perceptual alternations. These findings demonstrate a direct relationship between structure of SPL and individuals' perceptual switch rate.
Graphical Abstract
Highlights
► Structure of superior parietal lobe (SPL) predicts switch rate in perceptual rivalry ► White-matter integrity in SPL correlates with individuals' switch rate ► Deactivation of SPL with transcranial magnetic stimulation slows perceptual rivalry
doi:10.1016/j.cub.2010.07.027
PMCID: PMC2949566  PMID: 20727757
SYSNEURO
6.  Development of the action observation network during early adolescence: a longitudinal study 
Adolescence places high demands on inter-personal interactions and, hence, on the extraction and processing of social cues. Here we assess longitudinally the development of brain activity within a network implicated in social cognition—the action observation network. We performed activation likelihood estimation meta-analyses to define regions of interest based upon the mature action observation network of adults. Using functional magnetic resonance imaging, we then examined developmental trajectories of functional brain activity within these brain regions. Using this approach, we reveal quadratic trajectories within a fronto-parietal network previously shown to demonstrate correlated morphological development.
doi:10.1093/scan/nsq105
PMCID: PMC3252627  PMID: 21278194
fMRI; development; adolescence; emotion; action observation
7.  Neural Correlates of Direct and Reflected Self-Appraisals in Adolescents and Adults: When Social Perspective-Taking Informs Self-Perception 
Child development  2009;80(4):1016-1038.
Classic theories of self-development suggest people define themselves in part through internalized perceptions of other people’s beliefs about them, known as reflected self-appraisals. This study uses functional magnetic resonance imaging to compare the neural correlates of direct and reflected self-appraisals in adolescence (N = 12, ages 11–14 years) and adulthood (N = 12, ages 23–30 years). During direct self-reflection, adolescents demonstrated greater activity than adults in networks relevant to self-perception (medial prefrontal and parietal cortices) and social-cognition (dorsomedial prefrontal cortex, temporal–parietal junction, and posterior superior temporal sulcus), suggesting adolescent self-construals may rely more heavily on others’ perspectives about the self. Activity in the medial fronto-parietal network was also enhanced when adolescents took the perspective of someone more relevant to a given domain.
doi:10.1111/j.1467-8624.2009.01314.x
PMCID: PMC3229828  PMID: 19630891
8.  Age-related cognitive gains are mediated by the effects of white matter development on brain network integration 
NeuroImage  2009;48(4):738-746.
A fundamental, yet rarely tested premise of developmental cognitive neuroscience is that changes in brain activity and improvements in behavioral control across adolescent development are related to brain maturational factors that shape a more efficient, highly-interconnected brain in adulthood. We present the first multimodal neuroimaging study to empirically demonstrate that maturation of executive cognitive ability is directly associated with the relationship of white matter development and age-related changes in neural network functional integration. In this study, we identified specific white matter regions whose maturation across adolescence appears to reduce reliance on local processing in brain regions recruited for conscious, deliberate cognitive control in favor of a more widely distributed profile of functionally-integrated brain activity. Greater white matter coherence with age was associated with both increases and decreases in functional connectivity within task-engaged functional circuits. Importantly, these associations between white matter development and brain system functional integration were related to behavioral performance on tests of response inhibition, demonstrating their importance in the maturation of optimal cognitive control.
doi:10.1016/j.neuroimage.2009.06.065
PMCID: PMC2753497  PMID: 19577651
CONNECTIVITY; DIFFUSION TENSOR IMAGING; NETWORK; RESPONSE INHIBITION; DEVELOPMENT; ADOLESCENT
9.  Altered Causal Connectivity of Resting State Brain Networks in Amnesic MCI 
PLoS ONE  2014;9(3):e88476.
Most neuroimaging studies of resting state networks in amnesic mild cognitive impairment (aMCI) have concentrated on functional connectivity (FC) based on instantaneous correlation in a single network. The purpose of the current study was to investigate effective connectivity in aMCI patients based on Granger causality of four important networks at resting state derived from functional magnetic resonance imaging data – default mode network (DMN), hippocampal cortical memory network (HCMN), dorsal attention network (DAN) and fronto-parietal control network (FPCN). Structural and functional MRI data were collected from 16 aMCI patients and 16 age, gender-matched healthy controls. Correlation-purged Granger causality analysis was used, taking gray matter atrophy as covariates, to compare the group difference between aMCI patients and healthy controls. We found that the causal connectivity between networks in aMCI patients was significantly altered with both increases and decreases in the aMCI group as compared to healthy controls. Some alterations were significantly correlated with the disease severity as measured by mini-mental state examination (MMSE), and California verbal learning test (CVLT) scores. When the whole-brain signal averaged over the entire brain was used as a nuisance co-variate, the within-group maps were significantly altered while the between-group difference maps did not. These results suggest that the alterations in causal influences may be one of the possible underlying substrates of cognitive impairments in aMCI. The present study extends and complements previous FC studies and demonstrates the coexistence of causal disconnection and compensation in aMCI patients, and thus might provide insights into biological mechanism of the disease.
doi:10.1371/journal.pone.0088476
PMCID: PMC3948954  PMID: 24613934
10.  Resting-State Functional Connectivity between Fronto-Parietal and Default Mode Networks in Obsessive-Compulsive Disorder 
PLoS ONE  2012;7(5):e36356.
Background
Obsessive-compulsive disorder (OCD) is characterized by an excessive focus on upsetting or disturbing thoughts, feelings, and images that are internally-generated. Internally-focused thought processes are subserved by the “default mode network" (DMN), which has been found to be hyperactive in OCD during cognitive tasks. In healthy individuals, disengagement from internally-focused thought processes may rely on interactions between DMN and a fronto-parietal network (FPN) associated with external attention and task execution. Altered connectivity between FPN and DMN may contribute to the dysfunctional behavior and brain activity found in OCD.
Methods
The current study examined interactions between FPN and DMN during rest in 30 patients with OCD (17 unmedicated) and 32 control subjects (17 unmedicated). Timecourses from seven fronto-parietal seeds were correlated across the whole brain and compared between groups.
Results
OCD patients exhibited altered connectivity between FPN seeds (primarily anterior insula) and several regions of DMN including posterior cingulate cortex, medial frontal cortex, posterior inferior parietal lobule, and parahippocampus. These differences were driven largely by a reduction of negative correlations among patients compared to controls. Patients also showed greater positive connectivity between FPN and regions outside DMN, including thalamus, lateral frontal cortex, and somatosensory/motor regions.
Conclusions
OCD is associated with abnormal intrinsic functional connectivity between large-scale brain networks. Alteration of interactions between FPN and DMN at rest may contribute to aspects of the OCD phenotype, such as patients' inability to disengage from internally-generated scenarios and thoughts when performing everyday tasks requiring external attention.
doi:10.1371/journal.pone.0036356
PMCID: PMC3343054  PMID: 22570705
11.  Early Cognitive and Language Skills are Linked to Resting Frontal Gamma Power Across the First Three Years 
Behavioural brain research  2008;195(2):215-222.
High-frequency cortical activity in humans and animals has been linked to a wide variety of higher cognitive processes. This research suggests that specific changes in neuronal synchrony occur during cognitive processing, distinguished by emergence of fast oscillations in the gamma frequency range. To determine whether the development of high-frequency brain oscillations can be related to the development of cognitive abilities, we studied the power spectra of resting EEG in children 16, 24 and 36 months of age. Individual differences in the distribution of frontal gamma power during rest were highly correlated with concurrent language and cognitive skills at all ages. Gamma power was also associated with attention measures; children who were observed as having better inhibitory control and more mature attention shifting abilities had higher gamma power density functions. We included a group of children with a family history of language impairment (FH+) and thus at higher risk for language disorders. FH+ children, as a group, showed consistently lower gamma over frontal regions than the well-matched FH- controls with no such family history (FH-). We suggest that the emergence of high frequency neural synchrony may be critical for cognitive and linguistic development, and that children at risk for language impairments may lag in this process.
doi:10.1016/j.bbr.2008.08.049
PMCID: PMC2610686  PMID: 18831992
language; cognitive development; resting EEG; gamma power; attention
12.  Identification of Genetically Mediated Cortical Networks: A Multivariate Study of Pediatric Twins and Siblings 
Cerebral Cortex (New York, NY)  2008;18(8):1737-1747.
Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.
doi:10.1093/cercor/bhm211
PMCID: PMC2790393  PMID: 18234689
child development; genetics; neuroanatomy; small world
13.  Identifying the neural correlates of executive functions in early cerebral microangiopathy: a combined VBM and DTI study 
Cerebral microangiopathy (CMA) has been associated with executive dysfunction and fronto-parietal neural network disruption. Advances in magnetic resonance imaging allow more detailed analyses of gray (e.g., voxel-based morphometry—VBM) and white matter (e.g., diffusion tensor imaging—DTI) than traditional visual rating scales. The current study investigated patients with early CMA and healthy control subjects with all three approaches. Neuropsychological assessment focused on executive functions, the cognitive domain most discussed in CMA. The DTI and age-related white matter changes rating scales revealed convergent results showing widespread white matter changes in early CMA. Correlations were found in frontal and parietal areas exclusively with speeded, but not with speed-corrected executive measures. The VBM analyses showed reduced gray matter in frontal areas. All three approaches confirmed the hypothesized fronto-parietal network disruption in early CMA. Innovative methods (DTI) converged with results from conventional methods (visual rating) while allowing greater spatial and tissue accuracy. They are thus valid additions to the analysis of neural correlates of cognitive dysfunction. We found a clear distinction between speeded and nonspeeded executive measures in relationship to imaging parameters. Cognitive slowing is related to disease severity in early CMA and therefore important for early diagnostics.
doi:10.1038/jcbfm.2012.96
PMCID: PMC3463884  PMID: 22781332
cerebrovascular disease; diffusion tensor imaging; MRI; vascular cognitive impairment; white matter disease
14.  Breastfeeding and early white matter development: A cross-sectional study☆ 
Neuroimage  2013;82(100):77-86.
Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10 months through 4 years of age, who were either exclusively breastfed a minimum of 3 months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.
Highlights
•First investigation of breast-feeding and early infant brain myelination.•Breastfed infants shown improved brain development by 2 years of age.•Duration of breastfeeding is positively associated with behavioral performance.
doi:10.1016/j.neuroimage.2013.05.090
PMCID: PMC3777218  PMID: 23721722
MCR, Multicomponent Relaxometry; MRI, Magnetic Resonance Imaging; MWF, Myelin Water Fraction; VFM, mcDESPOT Derived Myelin Water Fraction; T1, Longitudinal Relaxation Time; T2, Transverse Relation Time; Brain development; Breastfeeding; Myelin maturation; White matter development; Infant imaging; Myelin; Myelin water fraction; Magnetic resonance imaging
15.  Aging Brain from a Network Science Perspective: Something to Be Positive About? 
PLoS ONE  2013;8(11):e78345.
To better understand age differences in brain function and behavior, the current study applied network science to model functional interactions between brain regions. We observed a shift in network topology whereby for older adults subcortical and cerebellar structures overlapping with the Salience network had more connectivity to the rest of the brain, coupled with fragmentation of large-scale cortical networks such as the Default and Fronto-Parietal networks. Additionally, greater integration of the dorsal medial thalamus and red nucleus in the Salience network was associated with greater satisfaction with life for older adults, which is consistent with theoretical predictions of age-related increases in emotion regulation that are thought to help maintain well-being and life satisfaction in late adulthood. In regard to cognitive abilities, greater ventral medial prefrontal cortex coherence with its topological neighbors in the Default Network was associated with faster processing speed. Results suggest that large-scale organizing properties of the brain differ with normal aging, and this perspective may offer novel insight into understanding age-related differences in cognitive function and well-being.
doi:10.1371/journal.pone.0078345
PMCID: PMC3819386  PMID: 24223147
16.  Interactions between White Matter Asymmetry and Language during Neurodevelopment 
The Journal of Neuroscience  2013;33(41):16170-16177.
The human brain is asymmetric in gross structure as well as functional organization. However, the developmental basis and trajectory of this asymmetry is unclear, and its relationship(s) to functional and cognitive development, especially language, remain to be fully elucidated. During infancy and early childhood, in concert with cortical gray matter growth, underlying axonal bundles become progressively myelinated. This myelination is critical for efficient and coherent interneuronal communication and, as revealed in animal studies, the degree of myelination changes in response to environment and neuronal activity. Using a novel quantitative magnetic resonance imaging method to investigate myelin content in vivo in human infants and young children, we investigated gross asymmetry of myelin in a large cohort of 108 typically developing children between 1 and 6 years of age, hypothesizing that asymmetry would predict language abilities in this cohort. While asymmetry of myelin content was evident in multiple cortical and subcortical regions, language ability was predicted only by leftward asymmetry of caudate and frontal cortex myelin content and rightward asymmetry in the extreme capsule. Importantly, the influence of this asymmetry was found to change with age, suggesting an age-specific influence of structure and myelin on language function. The relationship between language ability and asymmetry of myelin stabilized at ∼4 years, indicating anatomical evidence for a critical time during development before which environmental influence on cognition may be greatest.
doi:10.1523/JNEUROSCI.1463-13.2013
PMCID: PMC3792458  PMID: 24107949
17.  Abnormal Structure–Function Relationship in Spasmodic Dysphonia 
Cerebral Cortex (New York, NY)  2011;22(2):417-425.
Spasmodic dysphonia (SD) is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. Although recent studies have found abnormal brain function and white matter organization in SD, the extent of gray matter alterations, their structure–function relationships, and correlations with symptoms remain unknown. We compared gray matter volume (GMV) and cortical thickness (CT) in 40 SD patients and 40 controls using voxel-based morphometry and cortical distance estimates. These measures were examined for relationships with blood oxygen level–dependent signal change during symptomatic syllable production in 15 of the same patients. SD patients had increased GMV, CT, and brain activation in key structures of the speech control system, including the laryngeal sensorimotor cortex, inferior frontal gyrus (IFG), superior/middle temporal and supramarginal gyri, and in a structure commonly abnormal in other primary dystonias, the cerebellum. Among these regions, GMV, CT and activation of the IFG and cerebellum showed positive relationships with SD severity, while CT of the IFG correlated with SD duration. The left anterior insula was the only region with decreased CT, which also correlated with SD symptom severity. These findings provide evidence for coupling between structural and functional abnormalities at different levels within the speech production system in SD.
doi:10.1093/cercor/bhr120
PMCID: PMC3256408  PMID: 21666131
cortical thickness; fMRI; laryngeal dystonia; VBM; voice production
18.  Functional network dysfunction in anxiety and anxiety disorders 
Trends in neurosciences  2012;35(9):527-535.
A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. Here, we propose that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies.
doi:10.1016/j.tins.2012.04.012
PMCID: PMC3432139  PMID: 22658924
Anxiety; Anxiety Disorder; Brain Network; Functional Network; fMRI
19.  Aberrant functional activation in school age children at-risk for mathematical disability: A functional imaging study of simple arithmetic skill 
Neuropsychologia  2009;47(12):2470-2479.
We used functional magnetic resonance imaging (fMRI) to explore the patterns of brain activation associated with different levels of performance in exact and approximate calculation tasks in well defined cohorts of children with mathematical calculation difficulties (MD) and typically developing controls. Both groups of children activated the same network of brain regions; however, children in the MD group had significantly increased activation in parietal, frontal, and cingulate cortices during both calculation tasks. A majority of the differences occurred in anatomical brain regions associated with cognitive resources such as executive functioning and working memory that are known to support higher level arithmetic skill but are not specific to mathematical processing. We propose that these findings are evidence that children with MD use the same types of problem solving strategies as TD children, but their weak mathematical processing system causes them to employ a more developmentally immature and less efficient form of the strategies.
doi:10.1016/j.neuropsychologia.2009.04.024
PMCID: PMC2712586  PMID: 19410589
arithmetic; development; mathematical skill; numerical processing; school-age; mathematical disability
20.  Internal representation of hierarchical sequences involves the default network 
BMC Neuroscience  2010;11:54.
Background
The default network is a set of brain regions that exhibit a reduction in BOLD response during attention-demanding cognitive tasks, and distinctive patterns of functional connectivity that typically include anti-correlations with a fronto-parietal network involved in attention, working memory, and executive control. The function of the default network regions has been attributed to introspection, self-awareness, and theory of mind judgments, and some of its regions are involved in episodic memory processes.
Results
Using the method of psycho-physiological interactions, we studied the functional connectivity of several regions in a fronto-parietal network involved in a paired image discrimination task involving transitive inference. Some image pairs were derived from an implicit underlying sequence A>B>C>D>E, and some were independent (F>G, H>J, etc). Functional connectivity between the fronto-parietal regions and the default network regions depended on the presence of the underlying sequence relating the images. When subjects viewed learned and novel pairs from the sequence, connectivity between these two networks was higher than when subjects viewed learned and novel pairs from the independent sets.
Conclusions
These results suggest that default network regions were involved in maintaining the internal model that subserved discrimination of image pairs derived from the implicit sequence, and contributed to introspective access of an internal sequence model built during training. The default network may not be a unified entity with a specific function, but rather may interact with other functional networks in task-dependent ways.
doi:10.1186/1471-2202-11-54
PMCID: PMC2868853  PMID: 20423509
21.  Control networks in paediatric Tourette syndrome show immature and anomalous patterns of functional connectivity 
Brain  2008;132(1):225-238.
Tourette syndrome (TS) is a developmental disorder characterized by unwanted, repetitive behaviours that manifest as stereotyped movements and vocalizations called ‘tics’. Operating under the hypothesis that the brain's control systems may be impaired in TS, we measured resting-state functional connectivity MRI (rs-fcMRI) between 39 previously defined putative control regions in 33 adolescents with TS. We were particularly interested in the effect of TS on two of the brain's task control networks—a fronto-parietal network likely involved in more rapid, adaptive online control, and a cingulo-opercular network apparently important for set-maintenance. To examine the relative maturity of connections in the Tourette subjects, functional connections that changed significantly over typical development were examined. Age curves were created for each functional connection charting correlation coefficients over age for 210 healthy people aged 7–31 years, and the TS group correlation coefficients were compared to these curves. Many of these connections were significantly less ‘mature’ than expected in the TS group. This immaturity was true not only for functional connections that grow stronger with age, but also for those that diminish in strength with age. To explore other differences between Tourette and typically developing subjects further, we performed a second analysis in which the TS group was directly compared to an age-matched, movement-matched group of typically developing, unaffected adolescents. A number of functional connections were found to differ between the two groups. For these identified connections, a large number of connectional differences were found where the TS group value was out of range compared to typical developmental age curves. These anomalous connections were primarily found in the fronto-parietal network, thought to be important for online adaptive control. These results suggest that in adolescents with TS, immature functional connectivity is widespread, with additional, more profound deviation of connectivity in regions related to adaptive online control.
doi:10.1093/brain/awn223
PMCID: PMC2638693  PMID: 18952678
Tourette syndrome; functional connectivity; attentional control; adolescence; cognitive development
22.  White Matter Tract Integrity Predicts Visual Search Performance in Young and Older Adults 
Neurobiology of aging  2011;33(2):433.e21-433.e31.
Functional imaging research has identified fronto-parietal attention networks involved in visual search, with mixed evidence regarding whether different networks are engaged when the search target differs from distracters by a single (elementary) versus multiple (conjunction) features. Neural correlates of visual search, and their potential dissociation, were examined here using integrity of white matter connecting the fronto-parietal networks. The effect of aging on these brain-behavior relationships was also of interest. Younger and older adults performed a visual search task and underwent diffusion tensor imaging (DTI) to reconstruct two fronto-parietal (superior and inferior longitudinal fasciculus, SLF and ILF) and two midline (genu, splenium) white matter tracts. As expected, results revealed age-related declines in conjunction, but not elementary, search performance; and in ILF and genu tract integrity. Importantly, integrity of the SLF, ILF, and genu tracts predicted search performance (conjunction and elementary), with no significant age group differences in these relationships. Thus, integrity of white matter tracts connecting fronto-parietal attention networks contributes to search performance in younger and older adults.
doi:10.1016/j.neurobiolaging.2011.02.001
PMCID: PMC3117024  PMID: 21402431
23.  Imaging Brain Fatigue from Sustained Mental Workload: An ASL Perfusion Study of the Time-On-Task Effect 
NeuroImage  2009;49(4):3426-3435.
During sustained periods of a taxing cognitive workload, humans typically display time-on-task (TOT) effects, in which performance gets steadily worse over the period of task engagement. Arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) was used in this study to investigate the neural correlates of TOT effects in a group of 15 subjects as they performed a 20-minute continuous psychomotor vigilance test (PVT). Subjects displayed significant TOT effects, as seen in progressively slower reaction times and significantly increased mental fatigue ratings after the task. Perfusion data showed that the PVT activates a right lateralized fronto-parietal attentional network in addition to the basal ganglia and sensorimotor cortices. The fronto-parietal network was less active during post-task rest compared to pre-task rest, and regional CBF decrease in this network correlated with performance decline. These results demonstrate the persistent effects of cognitive fatigue in the fronto-parietal network after a period of heavy mental work and indicate the critical role of this attentional network in mediating TOT effects. Furthermore, resting regional CBF in the thalamus and right middle frontal gyrus prior to task onset was predictive of subjects' subsequent performance decline, suggesting that resting CBF quantified by ASL perfusion fMRI may be a useful indicator of performance potential and a marker of the level of fatigue in the neural attentional system.
doi:10.1016/j.neuroimage.2009.11.020
PMCID: PMC2830749  PMID: 19925871
Time-on-task effect; psychomotor vigilance test; ASL perfusion fMRI; fronto-parietal network
24.  Gray matter volumes and cognitive ability in the epileptogenic brain malformation of periventricular nodular heterotopia 
Epilepsy & behavior : E&B  2009;15(4):456-460.
Periventricular nodular heterotopia (PNH) is a brain malformation clinically characterized by the triad of epilepsy, normal intelligence, and dyslexia. We investigated the structure-function relationship between cerebral volumes and cognitive ability in this disorder by studying twelve PNH subjects and six controls using volumetric analysis of high-resolution anatomical MRI and neuropsychological testing. Total cerebral volumes and specific brain compartment volumes (gray matter, white matter, and CSF) in PNH subjects were comparable to those in controls. There was a negative correlation between heterotopic gray matter volume and cortical gray matter volume. Cerebral and cortical volumes in PNH did not correlate with full-scale IQ, unlike in normal individuals. Our findings support the idea that heterotopic nodules contain misplaced neurons that would normally have migrated to the cortex, and suggest that structural correlates of normal cognitive ability may be different in the setting of neuronal migration failure.
doi:10.1016/j.yebeh.2009.05.009
PMCID: PMC2721909  PMID: 19541546
Periventricular nodular heterotopia; malformation of cortical development; volumetric MRI; intelligence
25.  Anatomic Magnetic Resonance Imaging of the Developing Child and Adolescent Brain and Effects of Genetic Variation 
Neuropsychology Review  2010;20(4):349-361.
Magnetic resonance imaging studies have begun to map effects of genetic variation on trajectories of brain development. Longitudinal studies of children and adolescents demonstrate a general pattern of childhood peaks of gray matter followed by adolescent declines, functional and structural increases in connectivity and integrative processing, and a changing balance between limbic/subcortical and frontal lobe functions, which extends well into young adulthood. Twin studies have demonstrated that genetic factors are responsible for a significant amount of variation in pediatric brain morphometry. Longitudinal studies have shown specific genetic polymorphisms affect rates of cortical changes associated with maturation. Although over-interpretation and premature application of neuroimaging findings for diagnostic purposes remains a risk, converging data from multiple imaging modalities is beginning to elucidate the influences of genetic factors on brain development and implications of maturational changes for cognition, emotion, and behavior.
doi:10.1007/s11065-010-9151-9
PMCID: PMC3268519  PMID: 21069466
Magnetic resonance imaging; Brain; Development; Genes; Twins

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