Rebecca S. Coalson

Prediction of Individual Brain Maturity Using fMRI

Connectivity Map of the Brain The growing appreciation that clinically abnormal behaviors in children and adolescents may be influenced or perhaps even initiated by developmental miscues has stoked an interest in mapping normal human brain maturation. Several groups have documented changes in gray and white matter using structural and functional magnetic resonance imaging (fMRI) in cross-sectional and longitudinal studies. Dosenbach et al. (p. 1358) developed an index of resting-state functional connectivity (that is, how tightly neuronal activities in distinct brain regions are correlated while the subject is at rest or even asleep) from analyses of three independent data sets (each based on fMRI scans of 150 to 200 individuals from ages 6 to 35 years old). Long-range connections increased with age and short-range connections decreased, indicating that networks become sparser and sharper with brain maturation. Multivariate pattern analysis of 5-minute brain scans provides a measure of brain maturity. Group functional connectivity magnetic resonance imaging (fcMRI) studies have documented reliable changes in human functional brain maturity over development. Here we show that support vector machine-based multivariate pattern analysis extracts sufficient information from fcMRI data to make accurate predictions about individuals’ brain maturity across development. The use of only 5 minutes of resting-state fcMRI data from 238 scans of typically developing volunteers (ages 7 to 30 years) allowed prediction of individual brain maturity as a functional connectivity maturation index. The resultant functional maturation curve accounted for 55% of the sample variance and followed a nonlinear asymptotic growth curve shape. The greatest relative contribution to predicting individual brain maturity was made by the weakening of short-range functional connections between the adult brain’s major functional networks.

The default mode network and self-referential processes in depression

The recently discovered default mode network (DMN) is a group of areas in the human brain characterized, collectively, by functions of a self-referential nature. In normal individuals, activity in the DMN is reduced during nonself-referential goal-directed tasks, in keeping with the folk-psychological notion of losing ones self in ones work. Imaging and anatomical studies in major depression have found alterations in both the structure and function in some regions that belong to the DMN, thus, suggesting a basis for the disordered self-referential thought of depression. Here, we sought to examine DMN functionality as a network in patients with major depression, asking whether the ability to regulate its activity and, hence, its role in self-referential processing, was impaired. To do so, we asked patients and controls to examine negative pictures passively and also to reappraise them actively. In widely distributed elements of the DMN [ventromedial prefrontal cortex prefrontal cortex (BA 10), anterior cingulate (BA 24/32), lateral parietal cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but not control subjects, exhibited a failure to reduce activity while both looking at negative pictures and reappraising them. Furthermore, looking at negative pictures elicited a significantly greater increase in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed than in control subjects. These data suggest depression is characterized by both stimulus-induced heightened activity and a failure to normally down-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.

A Developmental fMRI Study of Reading and Repetition Reveals Changes in Phonological and Visual Mechanisms Over Age

In this study of reading development, children (ages 7-10) and adults (ages 18-32) performed overt single-word reading and aural repetition tasks on high-frequency word stimuli during functional magnetic resonance imaging. Most regions showed similar activity across age groups. These widespread regions of similarity indicate that children and adults use largely overlapping mechanisms when processing high-frequency words. Significant task-related differences included greater activity in occipital cortex for the read task, and greater activity in temporal cortex for the repeat task; activity levels in these regions were similar for adults and children. However, age group differences were found in several posterior regions, including a set of regions implicated in adult reading: the left supramarginal gyrus, the left angular gyrus, and bilateral anterior extrastriate cortex. The angular and supramarginal gyrus regions, hypothesized to play a role in phonology, showed decreased activity in adults relative to children for high-frequency words. The extrastriate regions had significant activity for both the visual read task and auditory repeat task in children, but just for the read task in adults, showing significant task and age interactions. These results are consistent with decreasing reliance on phonological processing, and increasing tuning of visual mechanisms, with age.

Atypical resting-state functional connectivity of affective pain regions in chronic migraine.

Chronic migraineurs (CM) have painful intolerances to somatosensory, visual, olfactory, and auditory stimuli during and between migraine attacks. These intolerances are suggestive of atypical affective responses to potentially noxious stimuli. We hypothesized that atypical resting‐state functional connectivity (rs‐fc) of affective pain‐processing brain regions may associate with these intolerances. This study compared rs‐fc of affective pain‐processing regions in CM with controls.

Modulation of the brain’s functional network architecture in the transition from wake to sleep

The transition from quiet wakeful rest to sleep represents a period over which attention to the external environment fades. Neuroimaging methodologies have provided much information on the shift in neural activity patterns in sleep, but the dynamic restructuring of human brain networks in the transitional period from wake to sleep remains poorly understood. Analysis of electrophysiological measures and functional network connectivity of these early transitional states shows subtle shifts in network architecture that are consistent with reduced external attentiveness and increased internal and self-referential processing. Further, descent to sleep is accompanied by the loss of connectivity in anterior and posterior portions of the default-mode network and more locally organized global network architecture. These data clarify the complex and dynamic nature of the transitional period between wake and sleep and suggest the need for more studies investigating the dynamics of these processes.

Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis

OBJECTIVE Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. DESIGN Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls. RESULTS Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. CONCLUSION Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.

Interregional brain interactions in children with unilateral hearing loss.

Objective. To determine whether patterns of functional connectivity of cortical regions responsible for auditory processing and executive functions differ in children with unilateral hearing loss (UHL) versus their normal-hearing (NH) siblings. Study Design. Prospective observational study. Setting. Academic medical center. Subjects and Methods. Children with severe-to-profound UHL (9 right UHL, 7 left UHL) and 10 NH sibling controls were imaged using resting state functional connectivity magnetic resonance imaging (rs-fcMRI). All MRI images were transformed to a single common atlas; regions of interest (ROI) were chosen based on previous literature and unpublished results. Mean regionwise correlations and conjunction analyses were performed across 34 seed ROIs to identify temporally synchronized, low-frequency spontaneous fluctuations in the resting state blood oxygenation level–dependent signal that reveal functionally related regions. Results. Mean regionwise Student t tests found a left posterior opercular region with more correlated resting state activity with the inferior parietal lobule seed in the children with both left and right UHL than NH. In conjunction analysis, 4 regions showed different resting-state functional interactions between the NH and both UHL groups. These differences were in left medial globus pallidus, left middle temporal gyrus, right parahippocampal gyrus, and mid-cingulate cortex. These regions include areas associated with auditory processing, executive function, and memory formation. Conclusions. Resting state fcMRI identified differences in brain network interconnections between children with UHL and NH and may inform further investigation into the educational and behavioral difficulties experienced by children with UHL.

Unmasking Language Lateralization in Human Brain Intrinsic Activity

Lateralization of function is a fundamental feature of the human brain as exemplified by the left hemisphere dominance of language. Despite the prominence of lateralization in the lesion, split-brain and task-based fMRI literature, surprisingly little asymmetry has been revealed in the increasingly popular functional imaging studies of spontaneous fluctuations in the fMRI BOLD signal (so-called resting-state fMRI). Here, we show the global signal, an often discarded component of the BOLD signal in resting-state studies, reveals a leftward asymmetry that maps onto regions preferential for semantic processing in left frontal and temporal cortex and the right cerebellum and a rightward asymmetry that maps onto putative attention-related regions in right frontal, temporoparietal, and parietal cortex. Hemispheric asymmetries in the global signal resulted from amplitude modulation of the spontaneous fluctuations. To confirm these findings obtained from normal, healthy, right-handed subjects in the resting-state, we had them perform 2 semantic processing tasks: synonym and numerical magnitude judgment and sentence comprehension. In addition to establishing a new technique for studying lateralization through functional imaging of the resting-state, our findings shed new light on the physiology of the global brain signal.

Automated method for extracting response latencies of subject vocalizations in event-related fMRI experiments

For functional magnetic resonance imaging studies of the neural substrates of language, the ability to have subjects performing overt verbal responses while in the scanner environment is important for several reasons. Most directly, overt responses allow the investigator to measure the accuracy and reaction time of the behavior. One problem, however, is that magnetic resonance gradient noise obscures the audio recordings made of voice responses, making it difficult to discern subject responses and to calculate reaction times. ASSERT (Adaptive Spectral Subtraction for Extracting Response Times), an algorithm for removing MR gradient noise from audio recordings of subject responses, is described here. The signal processing improves intelligibility of the responses and also allows automated extraction of reaction times. The ASSERT-derived response times were comparable to manually measured times with a mean difference of -8.75 ms (standard deviation of difference = 26.2 ms). These results support the use of ASSERT for the purpose of extracting response latencies and scoring overt verbal responses.

Diffusion tensor imaging in children with unilateral hearing loss: a pilot study

Objective: Language acquisition was assumed to proceed normally in children with unilateral hearing loss (UHL) since they have one functioning ear. However, children with UHL score poorly on speech-language tests and have higher rates of educational problems compared to normal hearing (NH) peers. Diffusion tensor imaging (DTI) is an imaging modality used to measure microstructural integrity of brain white matter. The purpose of this pilot study was to investigate differences in fractional anisotropy (FA) and mean diffusivity (MD) in hearing- and non-hearing-related structures in the brain between children with UHL and their NH siblings. Study Design: Prospective observational cohort. Setting: Academic medical center. Subjects and Methods: Sixty one children were recruited, tested and imaged. Twenty nine children with severe-to-profound UHL were compared to 20 siblings with NH using IQ and oral language testing, and MRI with DTI. Twelve children had inadequate MRI data. Parents provided demographic data and indicated whether children had a need for an individualized educational program (IEP) or speech therapy (ST). DTI parameters were measured in auditory and non-auditory regions of interest (ROIs). Between-group comparisons were evaluated with non-parametric tests. Results: Lower FA of left lateral lemniscus was observed for children with UHL compared to their NH siblings, as well as trends toward differences in other auditory and non-auditory regions. Correlation analyses showed associations between several DTI parameters and outcomes in children with UHL. Regression analyses revealed relationships between educational outcome variables and several DTI parameters, which may provide clinically useful information for guidance of speech therapy. Discussion/Conclusion: Our data suggests that white matter microstructural patterns in several brain regions are preserved despite unilateral rather than bilateral auditory input which contrasts with findings in patients with bilateral hearing loss.