Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n ϭ 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n ϭ 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n ϭ 10) compared with older controls (n ϭ 29) showed high amyloid-␤ deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD.

Information processing in the human brain arises from both interactions between adjacent areas and from distant projections that form distributed brain systems. Here we map interactions across different spatial scales by estimating the degree of intrinsic functional connectivity for the local (≤14 mm) neighborhood directly surrounding brain regions as contrasted with distant (>14 mm) interactions. The balance between local and distant functional interactions measured at rest forms a map that separates sensorimotor cortices from heteromodal association areas and further identifies regions that possess both high local and distant cortical-cortical interactions. Map estimates of network measures demonstrate that high local connectivity is most often associated with a high clustering coefficient, long path length, and low physical cost. Task performance changed the balance between local and distant functional coupling in a subset of regions, particularly, increasing local functional coupling in regions engaged by the task. The observed properties suggest that the brain has evolved a balance that optimizes information-processing efficiency across different classes of specialized areas as well as mechanisms to modulate coupling in support of dynamically changing processing demands. We discuss the implications of these observations and applications of the present method for exploring normal and atypical brain function.

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Neurobiological models of obsessivecompulsive disorder (OCD) predict hyperactivity in brain circuits involving the orbitofrontal cortex and the basal ganglia, but it is unclear whether these areas are also characterized by altered brain network properties.Objectives: To determine regions of abnormal degree connectivity in patients with OCD and to investigate whether connectivity measures are affected by antidepressant medication in OCD.Design: Case-control cross-sectional study using restingstate functional magnetic resonance imaging and a datadriven, model-free method to test for alterations in the degree of whole-brain, distant, and local connectivity in unmedicated patients with OCD compared with healthy controls.Setting: Outpatient clinic for OCD.Participants: Twenty-three patients with OCD (12 women, 11 men) receiving no medication, 23 patients with OCD (14 women, 9 men) treated with antidepressant medication, and 2 equally sized control samples matched for age, sex, handedness, educational level, and IQ.Main Outcome Measures: Statistical parametric maps testing the degree of distant and local functional con-nectivity of each voxel (hub analysis at voxel level) and OCD symptom severity.Results: Unmedicated patients with OCD showed greater distant connectivity in the orbitofrontal cortex and subthalamic nucleus and greater local connectivity in the orbitofrontal cortex and the putamen. Furthermore, distant connectivity of the orbitofrontal cortex and the putamen positively correlated with global OCD symptom severity. Medicated patients with OCD showed reduced local connectivity of the ventral striatum compared with the unmedicated patients.Conclusions and Relevance: Consistent with neurobiological models of OCD, the orbitofrontal cortex and the basal ganglia are hyperconnected in unmedicated patients. The finding of distant connectivity alterations of the orbitofrontal cortex and the basal ganglia represents initial evidence of greater connections with distant cortical areas outside of corticostriatal circuitry. Furthermore, these data suggest that antidepressant medication may reduce connectivity within corticobasal gangliathalamo-cortical circuits in OCD.

Object Low-frequency components of the spontaneous functional MR imaging signal provide information about the intrinsic functional and anatomical organization of the brain. The ability to use such methods in individual patients may provide a powerful tool for presurgical planning. The authors explore the feasibility of presurgical motor function mapping in which a task-free paradigm is used. Methods Six surgical candidates with tumors or epileptic foci near the motor cortex participated in this study. The investigators directly compared task-elicited activation of the motor system to activation obtained from intrinsic activity correlations. The motor network within the unhealthy hemisphere was identified based on intrinsic activity correlations, allowing distortions of functional anatomy caused by the tumor and epilepsy to be directly visualized. The precision of the motor function mapping was further explored in 1 participant by using direct cortical stimulation. Results The motor regions localized based on the spontaneous activity correlations were quite similar to the regions defined by actual movement tasks and cortical stimulation. Using intrinsic activity correlations, it was possible to map the motor cortex in presurgical patients. Conclusions This task-free paradigm may provide a powerful approach to map functional anatomy in patients without task compliance and allow multiple brain systems to be determined in a single scanning session.

A wealth of neuroscience evidence demonstrates that aerobic fitness enhances structural brain plasticity, promoting the development of gray matter volume and maintenance of white matter integrity within networks for executive function, attention, learning, and memory. However, the role of aerobic fitness in shaping the functional brain connectome remains to be established. The present work therefore investigated the effects of aerobic fitness (as measured by VO2max) on individual differences in whole-brain functional connectivity assessed from resting state fMRI data. Using a connectome-wide association study, we identified significant brain-fitness relationships within a large sample of healthy young adults (N = 242). The results revealed several regions within frontal, temporal, parietal, and cerebellar cortex, having significant association with aerobic fitness. We further characterized the influence of these regions on 7 intrinsic connectivity networks, demonstrating the greatest association with networks that are known to mediate the beneficial effects of aerobic fitness on executive function (frontoparietal network), attention and learning (dorsal and ventral attention network), and memory (default mode network). In addition, we provide evidence that connectivity strength between these regions and the frontoparietal network is predictive of individuals' fluid intelligence.

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Abstract. In continuous-wave near-infrared spectroscopy (CW-NIRS), changes in the concentration of oxyhemoglobin and deoxyhemoglobin can be calculated by solving a set of linear equations from the modified Beer-Lambert Law. Cross-talk error in the calculated hemodynamics can arise from inaccurate knowledge of the wavelengthdependent differential path length factor (DPF). We apply the extended Kalman filter (EKF) with a dynamical systems model to calculate relative concentration changes in oxy-and deoxyhemoglobin while simultaneously estimating relative changes in DPF. Results from simulated and experimental CW-NIRS data are compared with results from a weighted least squares (WLSQ) method. The EKF method was found to effectively correct for artificially introduced errors in DPF and to reduce the cross-talk error in simulation. With experimental CW-NIRS data, the hemodynamic estimates from EKF differ significantly from the WLSQ (p < 0.001). The cross-correlations among residuals at different wavelengths were found to be significantly reduced by the EKF method compared to WLSQ in three physiologically relevant spectral bands 0.04 to 0.15 Hz, 0.15 to 0.4 Hz and 0.4 to 2.0 Hz (p < 0.001). This observed reduction in residual cross-correlation is consistent with reduced cross-talk error in the hemodynamic estimates from the proposed EKF method.