Faculty Bibliography

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.

The functional significance of the brain's white matter was not fully appreciated until new imaging methods were developed to visualize fiber pathways and connections in the living brain. Rapid advances in diffusion tensor imaging (DTI) have led to substantial insights into human brain development and disease processes and have thrust white matter into the focus of researchers and clinicians alike. The full clinical potential of this relatively new technique remains to be determined, but early indicators suggest that DTI will be a significant new technology in mapping mechanisms of human health and disease. Here we review brain changes that have been studied with DTI over the human lifespan and findings in a variety of neuropsychiatric disorders. We also suggest future areas where DTI is likely to have significant impact.

Research on resting-state functional connectivity reveals intrinsically connected networks in the brain that are largely consistent across the general population. However, there are individual differences in these networks that have not been elucidated. Here, we measured the influence of naturally occurring mood on functional connectivity. In particular, we examined the association between self-reported levels of anxiety and connectivity in the default mode network (DMN). Healthy youth (n=43; ages 10-18) and adult participants (n=24, ages 19-59) completed a 6-min resting-state functional magnetic resonance imaging scan, then immediately completed questionnaires assessing their mood and thoughts during the scan. Regression analyses conducted separately for the youth and adult samples revealed brain regions in which increases in connectivity differentially corresponded to higher anxiety in each group. In one area, the left insular cortex, both groups showed similar increased connectivity to the DMN (youth: -30, 26, 14; adults: -33, 12, 14) with increased anxiety. State anxiety assessed during scanning was not correlated with trait anxiety, so our results likely reflect state levels of anxiety. To our knowledge, this is the first study to relate naturally occurring mood to resting state connectivity.

Diffusion tensor imaging is widely used to evaluate the development of white matter. Information about how alterations in major neurotransmitter systems, such as the dopamine (DA) system, influence this development in healthy children, however, is lacking. Catechol-O-metyltransferase (COMT) is the major enzyme responsible for DA degradation in prefrontal brain structures, for which there is a corresponding genetic polymorphism (val158met) that confers either a more or less efficient version of this enzyme. The result of this common genetic variation is that children may have more or less available synaptic DA in prefrontal brain regions. In the present study we examined the relation between diffusion properties of frontal white matter structures and the COMT val158met polymorphism in 40 children ages 9-15. We found that the val allele was associated with significantly elevated fractional anisotropy values and reduced axial and radial diffusivities. These results indicate that the development of white matter in healthy children is related to COMT genotype and that alterations in white matter may be related to the differential availability of prefrontal DA. This investigation paves the way for further studies of how common functional variants in the genome might influence the development of brain white matter.

Recent evidence suggests that a genetic polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) mediates stress reactivity in adults. Little is known, however, about this gene-brain association in childhood and adolescence, generally conceptualized as a time of heightened stress reactivity. The present study examines the association between 5-HTTLPR allelic variation and responses to fearful and angry faces presented both sub- and supraliminally in participants, ages 9-17. Behaviorally, carriers of the 5-HTTLPR short (s) allele exhibited significantly greater attentional bias to subliminally presented fear faces than did their long (l)-allele homozygous counterparts. Moreover, s-allele carriers showed greater neural activations to fearful and angry faces than did l-allele homozygotes in various regions of association cortex previously linked to attention control in adults. These results indicate that in children and adolescents, s-allele carriers can be distinguished from l-allele homozygotes on the basis of hypervigilant behavioral and neural processing of negative material.