Faculty Bibliography

Activation likelihood estimation (ALE) meta-analyses allow investigators to integrate the results of multiple neuroimaging studies, potentially yielding novel results that may not have been evident in the individual studies. Here, we provide a brief, introductory description of ALE methods for readers without extensive expertise in neuroimaging.

OBJECTIVE: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the present study examines this issue in adolescents with GAD. METHOD: Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. RESULTS: Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. CONCLUSIONS: These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states.

Aim Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long-term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention-deficit-hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. Method We present a retrospective, cross-sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Results Sixty-six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5y 4mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T >/= 60), and 14% reached levels consistent with those seen in children with ASDs (T >/= 75). These raised levels were not explained by NF1 disease severity or externalizing/internalizing behavioral disorders. There was a statistically significant relationship between symptoms of ADHD and ASD (chi(2) =9.11, df=1, p=0.003, phi=0.56). Particularly salient were the relationships between attention and hyperactivity deficits, with impairments in social awareness and social motivation. Interpretation We found that symptoms of ASD in our NF1 population were raised, consistent with previous reports. Further characterization of the specific ASD symptoms and their impact on daily function is fundamental to the development and implementation of effective interventions in this population, which will probably include a combination of medical and behavioral approaches.

OBJECTIVE: To test whether children with attention-deficit/hyperactivity disorder (ADHD), free of conduct disorder (CD) in childhood (mean = 8 years), have elevated risk-taking, accidents, and medical illnesses in adulthood (mean = 41 years); whether development of CD influences risk-taking during adulthood; and whether exposure to psychostimulants in childhood predicts cardiovascular disease. We hypothesized positive relationships between childhood ADHD and risky driving (in the past 5 years), risky sex (in the past year), and between risk-taking and medical conditions in adulthood; and that development of CD/antisocial personality (APD) would account for the link between ADHD and risk-taking. We report causes of death. METHOD: Prospective 33-year follow-up of 135 boys of white ethnicity with ADHD in childhood and without CD (probands), and 136 matched male comparison subjects without ADHD (comparison subjects; mean = 41 years), blindly interviewed by clinicians. RESULTS: In adulthood, probands had relatively more risky driving, sexually transmitted disease, head injury, and emergency department admissions (p< .05-.01). Groups did not differ on other medical outcomes. Lifetime risk-taking was associated with negative health outcomes (p = .01-.001). Development of CD/APD accounted for the relationship between ADHD and risk-taking. Probands without CD/APD did not differ from comparison subjects in lifetime risky behaviors. Psychostimulant treatment did not predict cardiac illness (p = .55). Probands had more deaths not related to specific medical conditions (p = .01). CONCLUSIONS: Overall, among children with ADHD, it is those who develop CD/APD who have elevated risky behaviors as adults. Over their lifetime, those who did not develop CD/APD did not differ from comparison subjects in risk-taking behaviors. Findings also provide support for long-term safety of early psychostimulant treatment.

Attention-deficit/hyperactivity disorder (ADHD) and Asperger's Syndrome (AS) share a heterogeneous cognitive profile. Studies assessing executive functions (EF) and social cognition in both groups have found preserved and impaired performances. These inconsistent findings would be partially explained by the cognitive variability reported in these disorders. First, the present study explored the inter-individual variability in EF and social cognition in both patient groups. Second, we compared differential characteristics and commonalities in the cognitive profiles of EF and social cognition between ADHD, AS and control adults. We assessed 22 patients with ADHD, 23 adults with AS and 21 matched typically developing subjects using different measures of EF (working memory, cognitive flexibility and multitasking) and social cognition (theory of mind and decision-making). Group comparisons and multiple case series analyses (MCSA) were conducted. The between-group comparisons showed an EF deficit in working memory in ADHD and a theory of mind (ToM) impairment in AS. The MCSA evidenced that, compared to controls, ADHD patients had a higher inter-individual variability in EF, while individuals with AS had a more heterogeneous profile in social cognition tasks compared to both groups. Finally, the AS and ADHD groups presented higher task-related variability compared to controls and shared a common heterogeneous profile in EF. This is the first study to compare variability in EF and social cognition profiles of ADHD and AS. We propose that heterogeneity in EF performance is a link between ADHD and AS which may explain the overlap of symptomatology between both diagnoses. In addition, patients with AS seem to show a unique heterogeneous profile in ToM which may explain the low probability of finding AS symptoms in patients with ADHD.

While researchers have extensively characterized functional connectivity between brain regions, the characterization of functional homogeneity within a region of the brain connectome is in early stages of development. Several functional homogeneity measures were proposed previously, among which regional homogeneity (ReHo) was most widely used as a measure to characterize functional homogeneity of resting state fMRI (R-fMRI) signals within a small region (Zang et al., 2004). Despite a burgeoning literature on ReHo in the field of neuroimaging brain disorders, its test-retest (TRT) reliability remains unestablished. Using two sets of public R-fMRI TRT data, we systematically evaluated the ReHo's TRT reliability and further investigated the various factors influencing its reliability and found: 1) nuisance (head motion, white matter, and cerebrospinal fluid) correction of R-fMRI time series can significantly improve the TRT reliability of ReHo while additional removal of global brain signal reduces its reliability, 2) spatial smoothing of R-fMRI time series artificially enhances ReHo intensity and influences its reliability, 3) surface-based R-fMRI computation largely improves the TRT reliability of ReHo, 4) a scan duration of 5min can achieve reliable estimates of ReHo, and 5) fast sampling rates of R-fMRI dramatically increase the reliability of ReHo. Inspired by these findings and seeking a highly reliable approach to exploratory analysis of the human functional connectome, we established an R-fMRI pipeline to conduct ReHo computations in both 3-dimensions (volume) and 2-dimensions (surface).

The brain's intrinsic functional architecture, revealed in correlated spontaneous activity, appears to constitute a faithful representation of its repertoire of evoked, extrinsic functional interactions. Here, using broad task contrasts to probe evoked patterns of coactivation, we demonstrate tight coupling between the brain's intrinsic and extrinsic functional architectures for default and task-positive regions, but not for subcortical and limbic regions or for primary sensory and motor cortices. While strong correspondence likely reflects persistent or recurrent patterns of evoked coactivation, weak correspondence may exist for regions whose patterns of evoked functional interactions are more adaptive and context dependent. These findings were independent of task. For tight task contrasts (e.g., incongruent vs. congruent trials), evoked patterns of coactivation were unrelated to the intrinsic functional architecture, suggesting that high-level task demands are accommodated by context-specific modulations of functional interactions. We conclude that intrinsic approaches provide only a partial understanding of the brain's functional architecture. Appreciating the full repertoire of dynamic neural responses will continue to require task-based functional magnetic resonance imaging approaches.