Amanda Elton

Functional Network Development During the First Year: Relative Sequence and Socioeconomic Correlations

The first postnatal year is characterized by the most dramatic functional network development of the human lifespan. Yet, the relative sequence of the maturation of different networks and the impact of socioeconomic status (SES) on their development during this critical period remains poorly characterized. Leveraging a large, normally developing infant sample with multiple longitudinal resting-state functional magnetic resonance imaging scans during the first year (N = 65, scanned every 3 months), we aimed to delineate the relative maturation sequence of 9 key brain functional networks and examine their SES correlations. Our results revealed a maturation sequence from primary sensorimotor/auditory to visual to attention/default-mode, and finally to executive control networks. Network-specific critical growth periods were also identified. Finally, marginally significant positive SES-brain correlations were observed at 6 months of age for both the sensorimotor and default-mode networks, indicating interesting SES effects on functional brain maturation. To the best of our knowledge, this is the first study delineating detailed longitudinal growth trajectories of all major functional networks during the first year of life and their SES correlations. Insights from this study not only improve our understanding of early brain development, but may also inform the critical periods for SES expression during infancy.

Childhood maltreatment is associated with a sex-dependent functional reorganization of a brain inhibitory control network

Childhood adversity represents a major risk factor for drug addiction and other mental disorders. However, the specific mechanisms by which childhood adversity impacts human brain organization to confer greater vulnerability for negative outcomes in adulthood is largely unknown. As an impaired process in drug addiction, inhibitory control of behavior was investigated as a target of childhood maltreatment (abuse and neglect). Forty adults without Axis‐I psychiatric disorders (21 females) completed a Childhood Trauma Questionnaire (CTQ) and underwent functional MRI (fMRI) while performing a stop‐signal task. A group independent component analysis identified a putative brain inhibitory control network. Graph theoretical analyses and structural equation modeling investigated the impact of childhood maltreatment on the functional organization of this neural processing network. Graph theory outcomes revealed sex differences in the relationship between network functional connectivity and inhibitory control which were dependent on the severity of childhood maltreatment exposure. A network effective connectivity analysis indicated that a maltreatment dose‐related negative modulation of dorsal anterior cingulate (dACC) activity by the left inferior frontal cortex (IFC) predicted better response inhibition and lesser attention deficit hyperactivity disorder (ADHD) symptoms in females, but poorer response inhibition and greater ADHD symptoms in males. Less inhibition of the right IFC by dACC in males with higher CTQ scores improved inhibitory control ability. The childhood maltreatment‐related reorganization of a brain inhibitory control network provides sex‐dependent mechanisms by which childhood adversity may confer greater risk for drug use and related disorders and by which adaptive brain responses protect individuals from this risk factor. Hum Brain Mapp 35:1654–1667, 2014.

Altered functional connectivity of the insular cortex across prefrontal networks in cocaine addiction

Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. Participants comprised 41 patients with cocaine dependence and 19 controls who underwent a resting-state 3-T functional magnetic resonance imaging scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial prefrontal cortex, inferior frontal gyrus, and bilateral dorsolateral prefrontal cortex. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process.

Intersubject Variability of and Genetic Effects on the Brain's Functional Connectivity during Infancy

Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brains functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brains functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brains functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy.

Task-related modulation of functional connectivity variability and its behavioral correlations.

Two new directions of functional connectivity investigation are emerging to advance studies of the brains functional organization. First, the identification of task‐related dynamics of functional connectivity has elicited a growing interest in characterizing the brains functional reorganization due to task demands. Second, the nonstationarity of functional connectivity [i.e., functional connectivity variability (FCV)] within a single brain state has been increasingly recognized and studied. However, a combined investigation of these two avenues of research to explore the potential task‐modulation of FCV is lacking, which, nevertheless, could both improve our understanding of the potential sources of FCV and also reveal new strategies to study the neural correlates of task performance. In this study, 19 human subjects underwent four functional magnetic resonance imaging (fMRI) scans including both resting and task states to study task‐related modulation of FCV. Consistent with the hypothesis that FCV is partly underpinned by unconstrained mind wandering, FCV demonstrated significant task‐related decreases measured at the regional, network and system levels, which was greater for between‐network interactions than within‐network connections. Conversely, there remained a significant degree of residual variability during the task scans, suggesting that FCV is not specific to the resting state and likely includes an intrinsic, physiologically driven component. Finally, the degree of task‐induced decreases in FCV was significantly correlated with task performance accuracy, supporting its behavior significance. Overall, task modulation of FCV may represent an important direction for future studies, not only to provide insight into normal brain functioning but also to reveal potential biomarkers of various brain disorders. Hum Brain Mapp 36:3260–3272, 2015.

Task-positive functional connectivity of the default mode network transcends task domain

The default mode network (DMN) was first recognized as a set of brain regions demonstrating consistently greater activity during rest than during a multitude of tasks. Originally, this network was believed to interfere with goal-directed behavior based on its decreased activity during many such tasks. More recently, however, the role of the DMN during goal-directed behavior was established for internally oriented tasks, in which the DMN demonstrated increased activity. However, the well-documented hub position and information-bridging potential of midline DMN regions indicate that there is more to uncover regarding its functional contributions to goal-directed tasks, which may be based on its functional interactions rather than its level of activation. An investigation of task-related changes in DMN functional connectivity during a series of both internal and external tasks would provide the requisite investigation for examining the role of the DMN during goal-directed task performance. In this study, 20 participants underwent fMRI while performing six tasks spanning diverse internal and external domains in addition to a resting-state scan. We hypothesized that the DMN would demonstrate “task-positive” (i.e., positively contributing to task performance) changes in functional connectivity relative to rest regardless of the direction of task-related changes in activity. Indeed, our results demonstrate significant increases in DMN connectivity with task-promoting regions (e.g., anterior insula, inferior frontal gyrus, middle frontal gyrus) across all six tasks. Furthermore, canonical correlation analyses indicated that the observed task-related connectivity changes were significantly associated with individual differences in task performance. Our results indicate that the DMN may not only support a “default” mode but may play a greater role in both internal and external tasks through flexible coupling with task-relevant brain regions.

Network Connectivity Abnormality Profile Supports a Categorical-Dimensional Hybrid Model of ADHD

Attention‐deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity, but there is no consensus regarding whether ADHD exists on the extreme end of a continuum of normal behavior or represents a discrete disorder. In this study, we sought to characterize both the categorical and dimensional variations in network functional connectivity in order to identify neural connectivity mechanisms of ADHD. Functional connectivity analyses of resting‐state fMRI data from 155 children with ADHD and 145 typically developing children (TDC) defined the dorsal attention network (DA), default mode network (DM), salience processing network (SAL) and executive control network (CON). Regional alterations in connectivity associated with categorical diagnoses and dimensional symptom measures (inattention and hyperactivity/impulsivity) as well as their interaction were systematically characterized. Dimensional relationships between symptom severity measures and functional connectivity that did not differ between TDC and children with ADHD were observed for each network, supporting a dimensional characterization of ADHD. However, categorical differences in functional connectivity magnitude between TDC and children with ADHD were detected after accounting for dimensional relationships, indicating the existence of categorical mechanisms independent of dimensional effects. Additionally, differential dimensional relationships for TDC versus ADHD children demonstrated categorical differences in brain–behavior relationships. The patterns of network functional organization associated with categorical versus dimensional measures of ADHD accentuate the complexity of this disorder and support a dual characterization of ADHD etiology featuring both dimensional and categorical mechanisms. Hum Brain Mapp 35:4531–4543, 2014.

Individual Differences in Attentional Bias Associated with Cocaine Dependence Are Related to Varying Engagement of Neural Processing Networks

Cocaine and other drug dependencies are associated with significant attentional bias for drug use stimuli that represents a candidate cognitive marker of drug dependence and treatment outcomes. We explored, using fMRI, the role of discrete neural processing networks in the representation of individual differences in the drug attentional bias effect associated with cocaine dependence (AB-coc) using a word counting Stroop task with personalized cocaine use stimuli (cocStroop). The cocStroop behavioral and neural responses were further compared with those associated with a negative emotional word Stroop task (eStroop) and a neutral word counting Stroop task (cStroop). Brain–behavior correlations were explored using both network-level correlation analysis following independent component analysis (ICA) and voxel-level, brain-wide univariate correlation analysis. Variation in the attentional bias effect for cocaine use stimuli among cocaine-dependent men and women was related to the recruitment of two separate neural processing networks related to stimulus attention and salience attribution (inferior frontal–parietal–ventral insula), and the processing of the negative affective properties of cocaine stimuli (frontal–temporal–cingulate). Recruitment of a sensory–motor–dorsal insula network was negatively correlated with AB-coc and suggested a regulatory role related to the sensorimotor processing of cocaine stimuli. The attentional bias effect for cocaine stimuli and for negative affective word stimuli were significantly correlated across individuals, and both were correlated with the activity of the frontal–temporal–cingulate network. Functional connectivity for a single prefrontal–striatal–occipital network correlated with variation in general cognitive control (cStroop) that was unrelated to behavioral or neural network correlates of cocStroop- or eStroop-related attentional bias. A brain-wide mass univariate analysis demonstrated the significant correlation of individual attentional bias effect for cocaine stimuli with distributed activations in the frontal, occipitotemporal, parietal, cingulate, and premotor cortex. These findings support the involvement of multiple processes and brain networks in mediating individual differences in risk for relapse associated with drug dependence.

Neural Connectivity Evidence for a Categorical-Dimensional Hybrid Model of Autism Spectrum Disorder

BACKGROUND Autism spectrum disorder (ASD) encompasses a complex manifestation of symptoms that include deficits in social interaction and repetitive or stereotyped interests and behaviors. In keeping with the increasing recognition of the dimensional characteristics of ASD symptoms and the categorical nature of a diagnosis, we sought to delineate the neural mechanisms of ASD symptoms based on the functional connectivity of four known neural networks (i.e., default mode network, dorsal attention network, salience network, and executive control network). METHODS We leveraged an open data resource (Autism Brain Imaging Data Exchange) providing resting-state functional magnetic resonance imaging data sets from 90 boys with ASD and 95 typically developing boys. This data set also included the Social Responsiveness Scale as a dimensional measure of ASD traits. Seed-based functional connectivity was paired with linear regression to identify functional connectivity abnormalities associated with categorical effects of ASD diagnosis, dimensional effects of ASD-like behaviors, and their interaction. RESULTS Our results revealed the existence of dimensional mechanisms of ASD uniquely affecting each network based on the presence of connectivity-behavioral relationships; these were independent of diagnostic category. However, we also found evidence of categorical differences (i.e., diagnostic group differences) in connectivity strength for each network as well as categorical differences in connectivity-behavioral relationships (i.e., diagnosis-by-behavior interactions), supporting the coexistence of categorical mechanisms of ASD. CONCLUSIONS Our findings support a hybrid model for ASD characterization that includes a combination of categorical and dimensional brain mechanisms and provide a novel understanding of the neural underpinnings of ASD.

Neural network activation during a stop‐signal task discriminates cocaine‐dependent from non‐drug‐abusing men

Cocaine dependence is defined by a loss of inhibitory control over drug‐use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural‐processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine‐dependent men and 27 healthy control men performed a stop‐signal task of motor inhibition. An independent component analysis on fMRI time courses identified task‐related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop‐signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine‐dependent men and 18 controls. Leave‐one‐out cross‐validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine‐dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine‐dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.