Faculty Bibliography

The network architecture of functional connectivity within the human brain connectome is poorly understood at the voxel level. Here, using resting state functional magnetic resonance imaging data from 1003 healthy adults, we investigate a broad array of network centrality measures to provide novel insights into connectivity within the whole-brain functional network (i.e., the functional connectome). We first assemble and visualize the voxel-wise (4 mm) functional connectome as a functional network. We then demonstrate that each centrality measure captures different aspects of connectivity, highlighting the importance of considering both global and local connectivity properties of the functional connectome. Beyond "detecting functional hubs," we treat centrality as measures of functional connectivity within the brain connectome and demonstrate their reliability and phenotypic correlates (i.e., age and sex). Specifically, our analyses reveal age-related decreases in degree centrality, but not eigenvector centrality, within precuneus and posterior cingulate regions. This implies that while local or (direct) connectivity decreases with age, connections with hub-like regions within the brain remain stable with age at a global level. In sum, these findings demonstrate the nonredundancy of various centrality measures and raise questions regarding their underlying physiological mechanisms that may be relevant to the study of neurodegenerative and psychiatric disorders.

BACKGROUND: Default network (DN) abnormalities have been identified in patients with chronic schizophrenia using "resting state" functional magnetic resonance imaging (R-fMRI). Here, we examined the integrity of the DN in patients experiencing their first episode of psychosis (FEP) compared with sex- and age-matched healthy controls. METHODS: We collected R-fMRI data from 19 FEP patients (mean age 24.9 +/- 4.8 yrs, 14 males) and 19 healthy controls (26.1 +/- 4.8 yrs, 14 males) at 3T. Following standard preprocessing, we examined the functional connectivity (FC) of two DN subsystems and the two DN hubs (P<0.0045, corrected). RESULTS: Patients with FEP exhibited abnormal FC that appeared largely restricted to the dorsomedial prefrontal cortex (dMPFC) DN subsystem. Relative to controls, FEP patients exhibited weaker positive FC between dMPFC and posterior cingulate cortex (PCC) and precuneus, extending laterally through the parietal lobe to the posterior angular gyrus. Patients with FEP exhibited weaker negative FC between the lateral temporal cortex and the intracalcarine cortex, bilaterally. The PCC and temporo-parietal junction also exhibited weaker negative FC with the right fusiform gyrus extending to the lingual gyrus and lateral occipital cortex, in FEP patients, compared to controls. By contrast, patients with FEP showed stronger negative FC between the temporal pole and medial motor cortex, anterior precuneus and posterior mid-cingulate cortex. CONCLUSIONS: Abnormalities in the dMPFC DN subsystem in patients with a FEP suggest that FC patterns are altered even in the early stages of psychosis.

Empirical evidence increasingly supports the hypothesis that patterns of intrinsic functional connectivity (iFC) are sculpted by a history of evoked coactivation within distinct neuronal networks. This, together with evidence of strong correspondence among the networks defined by iFC and those delineated using a variety of other neuroimaging techniques, suggests a fundamental brain architecture detectable across multiple functional and structural imaging modalities. Here, we leverage this insight to examine the functional organization of the human insula. We parcellated the insula on the basis of three distinct neuroimaging modalities - task-evoked coactivation, intrinsic (i.e., task-independent) functional connectivity, and gray matter structural covariance. Clustering of these three different covariance-based measures revealed a convergent elemental organization of the insula that likely reflects a fundamental brain architecture governing both brain structure and function at multiple spatial scales. While not constrained to be hierarchical, our parcellation revealed a pseudo-hierarchical, multiscale organization that was consistent with previous clustering and meta-analytic studies of the insula. Finally, meta-analytic examination of the cognitive and behavioral domains associated with each of the insular clusters obtained elucidated the broad functional dissociations likely underlying the topography observed. To facilitate future investigations of insula function across healthy and pathological states, the insular parcels have been made freely available for download via http://fcon_1000.projects.nitrc.org, along with the analytic scripts used to perform the parcellations.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 x 10(-8)) and 11q and 17p (P<1 x 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

Objectives.- Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the abnormalities of the white matter connectivity in autism. We aimed to focus on evaluating hemispheric asymmetry in autism spectrum disorders (ASD) using a Diffusion Tensor Imaging (DTI). Methods.- We examined the difference of white matter integrity between left and right hemispheres using the DTI in Korean boys with high functioning ASD and age and sex matched healthy controls. Results.- We found that the asymmetry of FA values between left and right hemispheres in inferior longitudinal fasciculus and inferior fronto-occipital fasciculus were significantly decreased in ASD group compared to controls. It mainly was due to reduced FA value of left hemisphere in ASD. Conclusions.- Our findings suggested that the ASD might have atypical hemispheric asymmetry of white matter integrity assessed with DTI. These findings will help on understanding of more advanced neurobiological basis underlying ASD

Knowledge of the long-term course of childhood Attention Deficit Hyperactivity Disorder (ADHD) is limited by the lack of longitudinal studies that extend beyond the third decade. Information about the later adult status of children with ADHD, one of the most common disorders of childhood, is important since the disorder is widely reported to persist through adulthood. Findings from a prospective 30 year longitudinal study addresses the extended course of ADHD. We report on the functional and psychiatric outcome of 135 males at mean age 41, diagnosed with ADHD at mean age of 8 (range, 6-12 years), and 136 non-ADHD males matched for age and SES, interviewed blindly by trained clinicians. As expected, ADHD at follow-up was significantly elevated in probands (P < 0.001). When the number of ADHD criteria is reduced, as recommended for ADHD in adults, rates rise in both groups. Other disorders significantly more prevalent in probands were:antisocial personality disorder (APD), drug (non-alcohol) disorders, and nicotine dependence. Childhood ADHD was not associated with elevated rates of mood or anxiety disorders in adulthood. Findings pertaining to other functional domains also will be presented. The extended clinical course of ADHD appears diagnostically specific, consisting of ADHD, APD and drug (non-alcohol) use disorders, supporting the validity of the ADHD diagnosis

In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a Phase 1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9+/-2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-min 3-T echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a flanker task. After regressing-out task-associated variance, we used the residual time series as "continuous resting-state data" for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model.

BACKGROUND: Emerging neuroscientific and genetic findings emphasize the dimensional rather than the categorical aspects of psychiatric disorders. However, the integration of dimensional approaches within the current categorical diagnostic framework remains unclear. Here, we used resting state functional magnetic resonance imaging to examine whether dimensional measures of psychiatric symptomatology capture brain-behavior relationships unaccounted for by categorical diagnoses. Additionally, we examined whether dimensional brain-behavior relationships are modified by the presence of a categorically defined illness, attention-deficit/hyperactivity disorder (ADHD). METHODS: Resting state functional magnetic resonance imaging scans were collected from 37 typically developing children (aged 10.2 +/- 2; 21 female subjects) and 37 children meeting DSM-IV Text Revision criteria for ADHD (9.7 +/- 2; 11 female subjects). Parent-rated Child Behavior Checklist Externalizing and Internalizing scores served as dimensional measures in our analyses of default network (DN) resting state functional connectivity (RSFC). RESULTS: Regardless of diagnosis, we observed several significant relationships between DN RSFC and both internalizing and externalizing scores. Increased internalizing scores were associated with stronger positive intra-DN RSFC, while increased externalizing scores were associated with reduced negative RSFC between DN and task-positive regions such as dorsal anterior cingulate cortex. Several of these brain-behavior relationships differed depending on the categorical presence of ADHD. CONCLUSIONS: Our findings suggest that while categorical diagnostic boundaries provide an inadequate basis for understanding the pathophysiology of psychiatric disorders, psychiatric illness cannot be viewed simply as an extreme of typical neural or behavioral function. Efforts to understand the neural underpinnings of psychiatric illness should incorporate both categorical and dimensional clinical assessments