Fumiko Hoeft

Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder.

OBJECTIVE Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder. METHOD Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation. RESULTS Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups. CONCLUSIONS These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.

Functional and morphometric brain dissociation between dyslexia and reading ability

In functional neuroimaging studies, individuals with dyslexia frequently exhibit both hypoactivation, often in the left parietotemporal cortex, and hyperactivation, often in the left inferior frontal cortex, but there has been no evidence to suggest how to interpret the differential relations of hypoactivation and hyperactivation to dyslexia. To address this question, we measured brain activation by functional MRI during visual word rhyme judgment compared with visual cross-hair fixation rest, and we measured gray matter morphology by voxel-based morphometry in dyslexic adolescents in comparison with (i) an age-matched group, and (ii) a reading-matched group younger than the dyslexic group but equal to the dyslexic group in reading performance. Relative to the age-matched group (n = 19; mean 14.4 years), the dyslexic group (n = 19; mean 14.4 years) exhibited hypoactivation in left parietal and bilateral fusiform cortices and hyperactivation in left inferior and middle frontal gyri, caudate, and thalamus. Relative to the reading-matched group (n = 12; mean 9.8 years), the dyslexic group (n = 12; mean 14.5 years) also exhibited hypoactivation in left parietal and fusiform regions but equal activation in all four areas that had exhibited hyperactivation relative to age-matched controls as well. In regions that exhibited atypical activation in the dyslexic group, only the left parietal region exhibited reduced gray matter volume relative to both control groups. Thus, areas of hyperactivation in dyslexia reflected processes related to the level of current reading ability independent of dyslexia. In contrast, areas of hypoactivation in dyslexia reflected functional atypicalities related to dyslexia itself, independent of current reading ability, and related to atypical brain morphology in dyslexia.

Neural systems predicting long-term outcome in dyslexia

Individuals with developmental dyslexia vary in their ability to improve reading skills, but the brain basis for improvement remains largely unknown. We performed a prospective, longitudinal study over 2.5 y in children with dyslexia (n = 25) or without dyslexia (n = 20) to discover whether initial behavioral or brain measures, including functional MRI (fMRI) and diffusion tensor imaging (DTI), can predict future long-term reading gains in dyslexia. No behavioral measure, including widely used and standardized reading and language tests, reliably predicted future reading gains in dyslexia. Greater right prefrontal activation during a reading task that demanded phonological awareness and right superior longitudinal fasciculus (including arcuate fasciculus) white-matter organization significantly predicted future reading gains in dyslexia. Multivariate pattern analysis (MVPA) of these two brain measures, using linear support vector machine (SVM) and cross-validation, predicted significantly above chance (72% accuracy) which particular child would or would not improve reading skills (behavioral measures were at chance). MVPA of whole-brain activation pattern during phonological processing predicted which children with dyslexia would improve reading skills 2.5 y later with >90% accuracy. These findings identify right prefrontal brain mechanisms that may be critical for reading improvement in dyslexia and that may differ from typical reading development. Brain measures that predict future behavioral outcomes (neuroprognosis) may be more accurate, in some cases, than available behavioral measures.

More Is Not Always Better: Increased Fractional Anisotropy of Superior Longitudinal Fasciculus Associated with Poor Visuospatial Abilities in Williams Syndrome

We used diffusion tensor imaging to examine white matter integrity in the dorsal and ventral streams among individuals with Williams syndrome (WS) compared with two control groups (typically developing and developmentally delayed) and using three separate analysis methods (whole brain, region of interest, and fiber tractography). All analysis methods consistently showed that fractional anisotropy (FA; a measure of microstructural integrity) was higher in the right superior longitudinal fasciculus (SLF) in WS compared with both control groups. There was a significant association with deficits in visuospatial construction and higher FA in WS individuals. Comparable increases in FA across analytic methods were not observed in the left SLF or the bilateral inferior longitudinal fasciculus in WS subjects. Together, these findings suggest a specific role of right SLF abnormality in visuospatial construction deficits in WS.

Neural Basis of Dyslexia: A Comparison between Dyslexic and Nondyslexic Children Equated for Reading Ability

Adults and children with developmental dyslexia exhibit reduced parietotemporal activation in functional neuroimaging studies of phonological processing. These studies used age-matched and/or intelligence quotient-matched control groups whose reading ability and scanner task performance were often superior to that of the dyslexic group. It is unknown, therefore, whether differences in activation reflect simply poorer performance in the scanner, the underlying level of reading ability, or more specific neural correlates of dyslexia. To resolve this uncertainty, we conducted a functional magnetic resonance imaging study, with a rhyme judgment task, in which we compared dyslexic children with two control groups: age-matched children and reading-matched children (younger normal readers equated for reading ability or scanner-performance to the dyslexic children). Dyslexic children exhibited reduced activation relative to both age-matched and reading-matched children in the left parietotemporal cortex and five other regions, including the right parietotemporal cortex. The dyslexic children also exhibited reduced activation bilaterally in the parietotemporal cortex when compared with children equated for task performance during scanning. Nine of the 10 dyslexic children exhibited reduced left parietotemporal activation compared with their individually selected age-matched or reading-matched control children. Additionally, normal reading fifth graders showed more activation in the same bilateral parietotemporal regions than normal-reading third graders. These findings indicate that the activation differences seen in the dyslexic children cannot be accounted for by either current reading level or scanner task performance, but instead represent a distinct developmental atypicality in the neural systems that support learning to read.

Neuroanatomy of Fragile X Syndrome Is Associated with Aberrant Behavior and the Fragile X Mental Retardation Protein (FMRP)

To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation‐1 protein and to aberrant cognition and behavior.

Resting-state functional connectivity of subgenual anterior cingulate cortex in depressed adolescents.

BACKGROUND Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD. METHODS Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC. RESULTS We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group. CONCLUSIONS Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.

GAT: A Graph-Theoretical Analysis Toolbox for Analyzing Between-Group Differences in Large-Scale Structural and Functional Brain Networks

In recent years, graph theoretical analyses of neuroimaging data have increased our understanding of the organization of large-scale structural and functional brain networks. However, tools for pipeline application of graph theory for analyzing topology of brain networks is still lacking. In this report, we describe the development of a graph-analysis toolbox (GAT) that facilitates analysis and comparison of structural and functional network brain networks. GAT provides a graphical user interface (GUI) that facilitates construction and analysis of brain networks, comparison of regional and global topological properties between networks, analysis of network hub and modules, and analysis of resilience of the networks to random failure and targeted attacks. Area under a curve (AUC) and functional data analyses (FDA), in conjunction with permutation testing, is employed for testing the differences in network topologies; analyses that are less sensitive to the thresholding process. We demonstrated the capabilities of GAT by investigating the differences in the organization of regional gray-matter correlation networks in survivors of acute lymphoblastic leukemia (ALL) and healthy matched Controls (CON). The results revealed an alteration in small-world characteristics of the brain networks in the ALL survivors; an observation that confirm our hypothesis suggesting widespread neurobiological injury in ALL survivors. Along with demonstration of the capabilities of the GAT, this is the first report of altered large-scale structural brain networks in ALL survivors.

Genetic influences on sociability: Heightened amygdala reactivity and event-related responses to positive social stimuli in Williams syndrome

Williams syndrome (WS) is a genetic disorder caused by a hemizygous microdeletion on chromosome 7q11.23. WS is associated with a compelling neurocognitive profile characterized by relative deficits in visuospatial function, relative strengths in face and language processing, and enhanced drive toward social engagement. We used a combined functional magnetic resonance imaging (fMRI) and event-related potential (ERP) approach to examine the neural basis of social responsiveness in WS participants to two types of social stimuli, negative (fearful) and positive (happy) emotional facial expressions. Here, we report a double dissociation consistent across both methods such that WS participants exhibited heightened amygdala reactivity to positive (happy) social stimuli and absent or attenuated amygdala reactivity to negative (fearful) social stimuli, compared with controls. The fMRI findings indicate that atypical social processing in WS may be rooted in altered development of disparate amygdalar nuclei that subserve different social functions. The ERP findings suggest that abnormal amygdala reactivity in WS may possibly function to increase attention to and encoding of happy expressions and to decrease arousal to fearful expressions. This study provides the first evidence that the genetic deletion associated with WS influences the function of the amygdala to be particularly responsive to socially appetitive stimuli.

Methods and Software for fMRI Analysis of Clinical Subjects

Global Scaling and Motion Regression Median filter, no scaling or motion regression Clinical subjects and children present a challenge for fMRI analysis because of the increased potential for head motions to affect the collected data. While modeling techniques have been described to reduce these effects, including corrections for small motions [1], large motions [2], rapid motions [3], noise spikes [4], and spontaneous deep breaths [5], no single software package addresses all of these artifact effects, which often co-occur in clinical subject data. In addition, it is difficult for a user to validate if a given method were successful for a particular subject. Our goals were to develop automated software tools that addressed all of the aforementioned artifacts, and to provide visualization tools to help users validate the results.