Publications

2013
Zhang Y, Whitfield-Gabrieli S, Christodoulou JA, Gabrieli JDE. Atypical balance between occipital and fronto-parietal activation for visual shape extraction in dyslexia. PLoS One. 2013;8 (6) :e67331.Abstract
Reading requires the extraction of letter shapes from a complex background of text, and an impairment in visual shape extraction would cause difficulty in reading. To investigate the neural mechanisms of visual shape extraction in dyslexia, we used functional magnetic resonance imaging (fMRI) to examine brain activation while adults with or without dyslexia responded to the change of an arrow's direction in a complex, relative to a simple, visual background. In comparison to adults with typical reading ability, adults with dyslexia exhibited opposite patterns of atypical activation: decreased activation in occipital visual areas associated with visual perception, and increased activation in frontal and parietal regions associated with visual attention. These findings indicate that dyslexia involves atypical brain organization for fundamental processes of visual shape extraction even when reading is not involved. Overengagement in higher-order association cortices, required to compensate for underengagment in lower-order visual cortices, may result in competition for top-down attentional resources helpful for fluent reading.
Christodoulou JA, Barnard ME, Del Tufo SN, Katzir T, Whitfield-Gabrieli S, Gabrieli JDE, Chang BS. Integration of gray matter nodules into functional cortical circuits in periventricular heterotopia. Epilepsy Behav. 2013;29 (2) :400-6.Abstract
Alterations in neuronal circuitry are recognized as an important substrate of many neurological disorders, including epilepsy. Patients with the developmental brain malformation of periventricular nodular heterotopia (PNH) often have both seizures and dyslexia, and there is evidence to suggest that aberrant neuronal connectivity underlies both of these clinical features. We used task-based functional MRI (fMRI) to determine whether heterotopic nodules of gray matter in this condition are integrated into functional cortical circuits. Blood oxygenation level-dependent (BOLD) fMRI was acquired in eight participants with PNH during the performance of reading-related tasks. Evidence of neural activation within heterotopic gray matter was identified, and regions of cortical coactivation were then mapped systematically. Findings were correlated with resting-state functional connectivity results and with performance on the fMRI reading-related tasks. Six participants (75%) demonstrated activation within at least one region of gray matter heterotopia. Cortical areas directly overlying the heterotopia were usually coactivated (60%), as were areas known to have functional connectivity to the heterotopia in the task-free resting state (73%). Six of seven (86%) primary task contrasts resulted in heterotopia activation in at least one participant. Activation was most commonly seen during rapid naming of visual stimuli, a characteristic impairment in this patient population. Our findings represent a systematic demonstration that heterotopic gray matter can be metabolically coactivated in a neuronal migration disorder associated with epilepsy and dyslexia. Gray matter nodules were most commonly coactivated with the anatomically overlying cortex and other regions with resting-state connectivity to heterotopia. These results have broader implications for understanding the network pathogenesis of both seizures and reading disabilities.
2012
Christodoulou JA, Walker LM, Del Tufo SN, Katzir T, Gabrieli JDE, Whitfield-Gabrieli S, Chang BS. Abnormal structural and functional brain connectivity in gray matter heterotopia. Epilepsia. 2012;53 (6) :1024-32.Abstract
PURPOSE: Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. METHODS: Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level-dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. KEY FINDINGS: A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). SIGNIFICANCE: Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.
Kovelman I, Norton ES, Christodoulou JA, Gaab N, Lieberman DA, Triantafyllou C, Wolf M, Whitfield-Gabrieli S, Gabrieli JDE. Brain basis of phonological awareness for spoken language in children and its disruption in dyslexia. Cereb Cortex. 2012;22 (4) :754-64.Abstract
Phonological awareness, knowledge that speech is composed of syllables and phonemes, is critical for learning to read. Phonological awareness precedes and predicts successful transition from language to literacy, and weakness in phonological awareness is a leading cause of dyslexia, but the brain basis of phonological awareness for spoken language in children is unknown. We used functional magnetic resonance imaging to identify the neural correlates of phonological awareness using an auditory word-rhyming task in children who were typical readers or who had dyslexia (ages 7-13) and a younger group of kindergarteners (ages 5-6). Typically developing children, but not children with dyslexia, recruited left dorsolateral prefrontal cortex (DLPFC) when making explicit phonological judgments. Kindergarteners, who were matched to the older children with dyslexia on standardized tests of phonological awareness, also recruited left DLPFC. Left DLPFC may play a critical role in the development of phonological awareness for spoken language critical for reading and in the etiology of dyslexia.
Immordino-Yang MH, Christodoulou JA, Singh V. Rest Is Not Idleness: Implications of the Brain's Default Mode for Human Development and Education. Perspect Psychol Sci. 2012;7 (4) :352-64.Abstract
When people wakefully rest in the functional MRI scanner, their minds wander, and they engage a so-called default mode (DM) of neural processing that is relatively suppressed when attention is focused on the outside world. Accruing evidence suggests that DM brain systems activated during rest are also important for active, internally focused psychosocial mental processing, for example, when recalling personal memories, imagining the future, and feeling social emotions with moral connotations. Here the authors review evidence for the DM and relations to psychological functioning, including associations with mental health and cognitive abilities like reading comprehension and divergent thinking. This article calls for research into the dimensions of internally focused thought, ranging from free-form daydreaming and off-line consolidation to intensive, effortful abstract thinking, especially with socioemotional relevance. It is argued that the development of some socioemotional skills may be vulnerable to disruption by environmental distraction, for example, from certain educational practices or overuse of social media. The authors hypothesize that high environmental attention demands may bias youngsters to focus on the concrete, physical, and immediate aspects of social situations and self, which may be more compatible with external attention. They coin the term constructive internal reflection and advocate educational practices that promote effective balance between external attention and internal reflection.
2011
Kitts RL, Christodoulou J, Goldman S. Promoting interdisciplinary collaboration: trainees addressing siloed medical education. Acad Psychiatry. 2011;35 (5) :317-21.Abstract
OBJECTIVE: Professional siloing within medical institutions has been identified as a problem in medical education, including resident training. The authors discuss how trainees from different disciplines can collaborate to address this problem. METHOD: A group of trainees from psychiatry, developmental medicine, neurology, and education came together to develop a community of practice (CoP) to promote interdisciplinary collaboration. RESULTS: A key outcome was the development of a seminar including speakers and attendees (N=20 to 35) from psychiatry, developmental medicine, neurology, and education. The CoP, developed in 2008, continues to grow and develop through their seminar, which fosters institution-wide interdisciplinary collaboration. CONCLUSION: In an attempt to break down interdisciplinary silos, a CoP and interdisciplinary seminar were created. Trainee organizers benefited from an educational context that embodied adult-learning theory and promoted lifelong learning. The unique seminar that was created continues to promote a community sense of learning and practice. Outcome measures are currently being used to objectively measure these efforts.
2010
Ghosh SS, Kakunoori S, Augustinack J, Nieto-Castanon A, Kovelman I, Gaab N, Christodoulou JA, Triantafyllou C, Gabrieli JDE, Fischl B. Evaluating the validity of volume-based and surface-based brain image registration for developmental cognitive neuroscience studies in children 4 to 11 years of age. Neuroimage. 2010;53 (1) :85-93.Abstract
Understanding the neurophysiology of human cognitive development relies on methods that enable accurate comparison of structural and functional neuroimaging data across brains from people of different ages. A fundamental question is whether the substantial brain growth and related changes in brain morphology that occur in early childhood permit valid comparisons of brain structure and function across ages. Here we investigated whether valid comparisons can be made in children from ages 4 to 11, and whether there are differences in the use of volume-based versus surface-based registration approaches for aligning structural landmarks across these ages. Regions corresponding to the calcarine sulcus, central sulcus, and Sylvian fissure in both the hemispheres were manually labeled on T1-weighted structural magnetic resonance images from 31 children ranging in age from 4.2 to 11.2years old. Quantitative measures of shape similarity and volumetric-overlap of these manually labeled regions were calculated when brains were aligned using a 12-parameter affine transform, SPM's nonlinear normalization, a diffeomorphic registration (ANTS), and FreeSurfer's surface-based registration. Registration error for normalization into a common reference framework across participants in this age range was lower than commonly used functional imaging resolutions. Surface-based registration provided significantly better alignment of cortical landmarks than volume-based registration. In addition, registering children's brains to a common space does not result in an age-associated bias between older and younger children, making it feasible to accurately compare structural properties and patterns of brain activation in children from ages 4 to 11.
2009
Raschle NM, Lee M, Buechler R, Christodoulou JA, Chang M, Vakil M, Stering PL, Gaab N. Making MR imaging child's play - pediatric neuroimaging protocol, guidelines and procedure. J Vis Exp. 2009;(29).Abstract
Within the last decade there has been an increase in the use of structural and functional magnetic resonance imaging (fMRI) to investigate the neural basis of human perception, cognition and behavior. Moreover, this non-invasive imaging method has grown into a tool for clinicians and researchers to explore typical and atypical brain development. Although advances in neuroimaging tools and techniques are apparent, (f)MRI in young pediatric populations remains relatively infrequent. Practical as well as technical challenges when imaging children present clinicians and research teams with a unique set of problems. To name just a few, the child participants are challenged by a need for motivation, alertness and cooperation. Anxiety may be an additional factor to be addressed. Researchers or clinicians need to consider time constraints, movement restriction, scanner background noise and unfamiliarity with the MR scanner environment. A progressive use of functional and structural neuroimaging in younger age groups, however, could further add to our understanding of brain development. As an example, several research groups are currently working towards early detection of developmental disorders, potentially even before children present associated behavioral characteristics. Various strategies and techniques have been reported as a means to ensure comfort and cooperation of young children during neuroimaging sessions. Play therapy, behavioral approaches and simulation, the use of mock scanner areas, basic relaxation and a combination of these techniques have all been shown to improve the participant's compliance and thus MRI data quality. Even more importantly, these strategies have proven to increase the comfort of families and children involved. One of the main advances of such techniques for the clinical practice is the possibility of avoiding sedation or general anesthesia (GA) as a way to manage children's compliance during MR imaging sessions. In the current video report, we present a pediatric neuroimaging protocol with guidelines and procedures that have proven to be successful to date in young children.
Christodoulou JA, Gaab N. Using and misusing neuroscience in education-related research. Cortex. 2009;45 (4) :555-7.

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