Faculty Bibliography

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.

BACKGROUND:Responses to stress vary greatly in young adolescents, and little is known about neural correlates of the stress response in youth. The purpose of this study was to examine whether variability in cortisol responsivity following a social stress test in young adolescents is associated with altered neural functional connectivity (FC) of the salience network (SN) measured during resting-state functional magnetic resonance imaging (rs-fMRI). METHODS:Forty-nine typically developing young adolescents participated in a social stress test during which they contributed salivary cortisol samples. Following this, they underwent rs-fMRI scanning. We examined the association of FC of the SN [composed of anterior cingulate cortex and bilateral anterior insula regions] with cortisol responsivity. RESULTS:Greater cortisol responsivity was significantly positively correlated with higher FC between subgenual anterior cingulate cortex (Cg25) and the SN, controlling for participant age. There were no regions of the brain that showed an inverse relation. CONCLUSIONS:Brain systems that have been implicated in autonomic arousal and that influence subjective feeling states show altered FC associated with stress responsivity in early life.

BACKGROUND:Major depressive disorder (MDD) has been associated reliably with ruminative responding; this kind of responding is composed of both maladaptive and adaptive components. Levels of activity in the default-mode network (DMN) relative to the task-positive network (TPN), as well as activity in structures that influence DMN and TPN functioning, may represent important neural substrates of maladaptive and adaptive rumination in MDD. METHODS:We used a unique metric to estimate DMN dominance over TPN from blood oxygenation level-dependent data collected during eyes-closed rest in 17 currently depressed and 17 never-disordered adults. We calculated correlations between this metric of DMN dominance over TPN and the depressive, brooding, and reflective subscales of the Ruminative Responses Scale, correcting for associations between these measures both with one another and with severity of depression. Finally, we estimated and compared across groups right fronto-insular cortex (RFIC) response during initiations of ascent in DMN and in TPN activity. RESULTS:In the MDD participants, increasing levels of DMN dominance were associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination. Moreover, our RFIC state-change analysis showed increased RFIC activation in the MDD participants at the onset of increases in TPN activity; conversely, healthy control participants exhibited increased RFIC response at the onset of increases in DMN activity. CONCLUSIONS:These findings support a formulation in which the DMN undergirds representation of negative, self-referential information in depression, and the RFIC, when prompted by increased levels of DMN activity, initiates an adaptive engagement of the TPN.

Magnetic resonance imaging (MRI) has been used to image the in utero fetus for the past 3 decades. Although not as commonplace as other patient-oriented MRI, it is a growing field and demonstrating a role in the clinical care of the fetus. Indeed, the body of literature involving fetal MRI exceeds 3000 published articles. Indeed, there is interest in accessing even the healthy fetus with MRI to further understand the development of humans during the fetal stage. On the horizon is fetal imaging using 3.0-T clinical systems. Although a clear path is not necessarily determined, experiments, theoretical calculations, advances in pulse sequence design, new hardware, and experience from imaging at 1.5 T help define the path.

Resting-state MRI (rs-fMRI) is a powerful procedure for studying whole-brain neural connectivity. In this study we provide the first empirical evidence of the longitudinal reliability of rs-fMRI in children. We compared rest-retest measurements across spatial, temporal and frequency domains for each of six cognitive and sensorimotor intrinsic connectivity networks (ICNs) both within and between scan sessions. Using Kendall'sW, concordance of spatial maps ranged from .60 to .86 across networks, for various derived measures. The Pearson correlation coefficient for temporal coherence between networks across all Time 1-Time 2 (T1/T2) z-converted measures was .66 (p<.001). There were no differences between T1/T2 measurements in low-frequency power of the ICNs. For the visual network, within-session T1 correlated with the T2 low-frequency power, across participants. These measures from resting-state data in children were consistent across multiple domains (spatial, temporal, and frequency). Resting-state connectivity is therefore a reliable method for assessing large-scale brain networks in children.