Faculty Bibliography

This paper presents a method for intensity inhomogeniety removal in fMRI studies of a moving subject. In such studies, subtle changes in signal as the subject moves in the presence of a bias field can be a significant confound for BOLD signal analysis. The proposed method avoids the need for a specific tissue model or assumptions about tissue homogeneity by making use of the multiple views of the underlying bias field provided by the subject's motion. A parametric bias field model is assumed and a regression model is used to estimate the basis function weights of this model. Quantitative evaluation of the effects of motion and noise in motion estimates are performed using simulated data. Results demonstrate the strength and robustness of the new method compared to the state of the art 4D nonparametric bias estimator (N4ITK). We also qualitatively demonstrate the impact of the method on resting state neuroimage analysis of a moving adult brain with simulated motion and bias fields, as well as on in vivo moving fetal fMRI.

The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

Effective navigation of the social world relies on the correct interpretation of facial emotions. This may be particularly important in formative years. Critically, literature examining the emergence of face processing in youth (children and adolescents) has focused on the neural and behavioral correlates of processing adult faces, which are relationally different from youth participants, and whose facial expressions may convey different meaning than faces of their peers. During a functional magnetic resonance imaging (fMRI) scan, we compared concurrent neural and behavioral responses as youth (N=25) viewed validated, emotionally varied (i.e., anger, fear, happy, and neutral) adult and child face stimuli. We observed that participants made fewer errors when matching adult, compared to child, face stimuli, and that while similar brain regions were involved in processing both adult and child faces, activation in the face processing neural network was greater for adult than child faces. This was true across emotions, and also when comparing neutral adult versus neutral child faces. Additionally, a valence by stimuli-type effect was observed within the amygdala. That is, within adult face stimuli, negative and neutral face stimuli elicited the largest effects, whereas within child face stimuli, happy face stimuli elicited the largest amygdala effects. Thus, heightened engagement of the amygdala was observed for happy child and angry adult faces, which may reflect age-specific salience of select emotions in early life. This study provides evidence that the relational age of the perceived face influences neural processing in youth.

The organization of the brain is highly plastic in fetal life. Establishment of healthy neural functional systems during the fetal period is essential to normal growth and development. Across the last several decades, remarkable progress has been made in understanding the development of human fetal functional brain systems. This is largely due to advances in imaging methodologies. Fetal neuroimaging began in the 1950-1970's with fetal electroencephalography (EEG) applied during labor. Later, in the 1980's, magnetoencephalography (MEG) emerged as an effective approach for investigating fetal brain function. Most recently, functional magnetic resonance imaging (fMRI) has arisen as an additional powerful approach for examining fetal brain function. This review will discuss major developmental findings from fetal imaging studies such as the maturation of prenatal sensory system functions, functional hemispheric asymmetry, and sensory-driven neurodevelopment. We describe how with improved imaging and analysis techniques, functional imaging of the fetus has the potential to assess the earliest point of neural maturation and provide insight into the patterning and sequence of normal and abnormal brain development.

The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain-behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective--population neuroscience--that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas.

OBJECTIVE:Compelling evidence indicates that disruption in functional connectivity (FC) in brain networks underlies many psychiatric and developmental disorders. Current theory posits that biological (i.e., cortisol) and environmental (i.e., stress) experiences in early life are strong determinants in the development of functional brain systems and formative in the genesis of such disorders. The objective of this study was to examine the extent to which individual differences in cortisol concentrations during FC magnetic resonance imaging (MRI) would map onto variability in hippocampal to default mode network (DMN) connectivity in typically developing youth. METHOD/METHODS:Salivary cortisol and FC MRI data were collected concurrently in 33 scan-naive 7- to 15-year-old participants. Twenty-nine of these participants previously completed the Trier Social Stress Test. Hippocampal to DMN FC and endogenous cortisol variability during MRI were examined. A possible association between MRI cortisol and cortisol response to the Trier Social Stress Test during the preceding visit or a participant's ratings of anxiety during MRI was tested. RESULTS:There were significant positive relations between MRI cortisol levels and measurements in the following 3 areas: hippocampal to DMN FC during the resting state, cortisol levels during the Trier Social Stress Test, and fear/anxiety ratings during MRI. Fear/anxiety ratings during MRI also related to self-reported anxiety on standardized measurements. CONCLUSIONS:This study shows for the first time that FC of the hippocampus is altered with changing cortisol responsivity in youth. Altered FC during the resting state may represent altered alertness or monitoring resulting from variation in glucocorticoid function in youth, which carries implications for the effect of stress on response monitoring and decision making.

OBJECTIVE:  We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. METHODS:  Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. RESULTS:  The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). CONCLUSIONS:  Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker.

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

BACKGROUND:Radiation and chemotherapy targeted to the central nervous system (CNS) can cause cognitive impairment, including impaired memory. These memory impairments may be referable to damage to hippocampal structures resulting from CNS treatment. PROCEDURE/METHODS:In the present study, we explored episodic memory and its neuroimaging correlates in 10 adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy and both systemic and intrathecal chemotherapy and 10 controls matched for age and sex, using a subsequent memory paradigm after episodic encoding of visual scenes. RESULTS:We report behavioral, structural, and functional changes in the brains of the adult survivors. They demonstrated poorer recognition memory, hippocampal atrophy, and altered blood oxygenation level-dependent (BOLD) signal in the hippocampus. Whole brain statistical map analysis revealed increased BOLD signal/activation in several brain regions during unsuccessful encoding in ALL survivors, potentially reflecting ineffective neural recruitment. Individual differences in memory performance in ALL participants were related to magnitude of BOLD response in regions associated with successful encoding. CONCLUSIONS:Taken together, these findings describe long term neuroimaging correlates of cognitive dysfunction after childhood exposure to CNS-targeted cancer therapies, suggesting enduring damage to episodic memory systems.

Vector autoregression (VAR) and structural equation modeling (SEM) are two popular brain-network modeling tools. VAR, which is a data-driven approach, assumes that connected regions exert time-lagged influences on one another. In contrast, the hypothesis-driven SEM is used to validate an existing connectivity model where connected regions have contemporaneous interactions among them. We present the two models in detail and discuss their applicability to FMRI data, and their interpretational limits. We also propose a unified approach that models both lagged and contemporaneous effects. The unifying model, structural vector autoregression (SVAR), may improve statistical and explanatory power, and avoid some prevalent pitfalls that can occur when VAR and SEM are utilized separately.