Can structure predict function at individual level in the human connectome?

Several studies predicting Functional Connectivity (FC) from Structural Connectivity (SC) at individual level have been published in recent years, each promising increased performance and utility. We investigated three of these studies, analyzing whether the results truly represent a meaningful individual-level mapping from SC to FC. Using data from the Human Connectome Project shared accross the three studies, we constructed a predictor by averaging FC of training data and analyzed its performance in the same way. In each case, we found that group average FC is an equivalent or better predictor of individual FC than the predictive models in terms of raw prediction performance. Furthermore, we showed that additional analyses performed by the authors of the three studies, in which they attempt to show that their predicted FC has value beyond raw prediction performance, could also be reproduced using the group average FC predictor. This makes it unclear whether any of the three methods represent a meaningful individual-level predictive model. We conclude that either the methods are not appropriate for the data, that the sample size is too small, or that the data does not contain sufficient information to learn a mapping from SC to FC. We advise future individual-level studies to explicitly report results in comparison to the performance of the group average, and carefully demonstrate that their predictions contain meaningful individual-level information. Finally, we believe that investigating alternatives for the construction of SC and FC may improve the chances of developing a meaningful individual-level mapping from SC to FC.

Working memory performance in glioma patients is associated with functional connectivity between the right dorsolateral prefrontal cortex and default mode network.

In healthy subjects, activity in the default mode network (DMN) and the frontoparietal network (FPN) has consistently been associated with working memory (WM). In particular, the dorsolateral prefrontal cortex (DLPFC) is important for WM. The functional-anatomical basis of WM impairment in glioma patients is, however, still poorly understood. We investigated whether WM performance of glioma patients is reflected in resting-state functional connectivity (FC) between the DMN and FPN, additionally focusing on the DLPFC. Resting-state functional MRI data were acquired from 45 glioma patients prior to surgery. WM performance was derived from a pre-operative N-back task. Scans were parcellated into ROIs using both the Gordon and Yeo atlas. FC was calculated as the average Pearson correlation between functional time series. The FC between right DLPFC and DMN was inversely related to WM performance for both the Gordon and Yeo atlas (p = .010). No association was found for FC between left DLPFC and DMN, nor between the whole FPN and DMN. The results are robust and not dependent on atlas choice or tumor location, as they hold for both the Gordon and Yeo atlases, and independently of location variables. Our findings show that WM performance of glioma patients can be quantified in terms of interactions between regions and large-scale networks that can be measured with resting-state fMRI. These group-based results are a necessary step toward development of biomarkers for clinical management of glioma patients, and provide additional evidence that global disruption of the DMN relates to cognitive impairment in glioma patients.

Subject-Specific Automatic Reconstruction of White Matter Tracts.

MRI-based tractography is still underexploited and unsuited for routine use in brain tumor surgery due to heterogeneity of methods and functional-anatomical definitions and above all, the lack of a turn-key system. Standardization of methods is therefore desirable, whereby an objective and reliable approach is a prerequisite before the results of any automated procedure can subsequently be validated and used in neurosurgical practice. In this work, we evaluated these preliminary but necessary steps in healthy volunteers. Specifically, we evaluated the robustness and reliability (i.e., test-retest reproducibility) of tractography results of six clinically relevant white matter tracts by using healthy volunteer data (N = 136) from the Human Connectome Project consortium. A deep learning convolutional network-based approach was used for individualized segmentation of regions of interest, combined with an evidence-based tractography protocol and appropriate post-tractography filtering. Robustness was evaluated by estimating the consistency of tractography probability maps, i.e., averaged tractograms in normalized space, through the use of a hold-out cross-validation approach. No major outliers were found, indicating a high robustness of the tractography results. Reliability was evaluated at the individual level. First by examining the overlap of tractograms that resulted from repeatedly processed identical MRI scans (N = 10, 10 iterations) to establish an upper limit of reliability of the pipeline. Second, by examining the overlap for subjects that were scanned twice at different time points (N = 40). Both analyses indicated high reliability, with the second analysis showing a reliability near the upper limit. The robust and reliable subject-specific generation of white matter tracts in healthy subjects holds promise for future validation of our pipeline in a clinical population and subsequent implementation in brain tumor surgery.

Modeling of intracerebral interictal epileptic discharges: Evidence for network interactions.

OBJECTIVE: The interictal epileptic discharges (IEDs) occurring in stereotactic EEG (SEEG) recordings are in general abundant compared to ictal discharges, but difficult to interpret due to complex underlying network interactions. A framework is developed to model these network interactions. METHODS: To identify the synchronized neuronal activity underlying the IEDs, the variation in correlation over time of the SEEG signals is related to the occurrence of IEDs using the general linear model. The interdependency is assessed of the brain areas that reflect highly synchronized neural activity by applying independent component analysis, followed by cluster analysis of the spatial distributions of the independent components. The spatiotemporal interactions of the spike clusters reveal the leading or lagging of brain areas. RESULTS: The analysis framework was evaluated for five successfully operated patients, showing that the spike cluster that was related to the MRI-visible brain lesions coincided with the seizure onset zone. The additional value of the framework was demonstrated for two more patients, who were MRI-negative and for whom surgery was not successful. CONCLUSIONS: A network approach is promising in case of complex epilepsies. SIGNIFICANCE: Analysis of IEDs is considered a valuable addition to routine review of SEEG recordings, with the potential to increase the success rate of epilepsy surgery.

Stability metrics for optic radiation tractography: Towards damage prediction after resective surgery.

BACKGROUND: An accurate delineation of the optic radiation (OR) using diffusion MR tractography may reduce the risk of a visual field deficit after temporal lobe resection. However, tractography is prone to generate spurious streamlines, which deviate strongly from neighboring streamlines and hinder a reliable distance measurement between the temporal pole and the Meyer's loop (ML-TP distance). NEW METHOD: Stability metrics are introduced for the automated removal of spurious streamlines near the Meyer's loop. Firstly, fiber-to-bundle coherence (FBC) measures can identify spurious streamlines by estimating their alignment with the surrounding streamline bundle. Secondly, robust threshold selection removes spurious streamlines while preventing an underestimation of the extent of the Meyer's loop. Standardized parameter selection is realized through test-retest evaluation of the variability in ML-TP distance. RESULTS: The variability in ML-TP distance after parameter selection was below 2mm for each of the healthy volunteers studied (N=8). The importance of the stability metrics is illustrated for epilepsy surgery candidates (N=3) for whom the damage to the Meyer's loop was evaluated by comparing the pre- and post-operative OR reconstruction. The difference between predicted and observed damage is in the order of a few millimeters, which is the error in measured ML-TP distance. COMPARISON WITH EXISTING METHOD(S): The stability metrics are a novel method for the robust estimate of the ML-TP distance. CONCLUSIONS: The stability metrics are a promising tool for clinical trial studies, in which the damage to the OR can be related to the visual field deficit that may occur after epilepsy surgery.

Quantifying the brain's sheet structure with normalized convolution.

The hypothesis that brain pathways form 2D sheet-like structures layered in 3D as "pages of a book" has been a topic of debate in the recent literature. This hypothesis was mainly supported by a qualitative evaluation of "path neighborhoods" reconstructed with diffusion MRI (dMRI) tractography. Notwithstanding the potentially important implications of the sheet structure hypothesis for our understanding of brain structure and development, it is still considered controversial by many for lack of quantitative analysis. A means to quantify sheet structure is therefore necessary to reliably investigate its occurrence in the brain. Previous work has proposed the Lie bracket as a quantitative indicator of sheet structure, which could be computed by reconstructing path neighborhoods from the peak orientations of dMRI orientation density functions. Robust estimation of the Lie bracket, however, is challenging due to high noise levels and missing peak orientations. We propose a novel method to estimate the Lie bracket that does not involve the reconstruction of path neighborhoods with tractography. This method requires the computation of derivatives of the fiber peak orientations, for which we adopt an approach called normalized convolution. With simulations and experimental data we show that the new approach is more robust with respect to missing peaks and noise. We also demonstrate that the method is able to quantify to what extent sheet structure is supported for dMRI data of different species, acquired with different scanners, diffusion weightings, dMRI sampling schemes, and spatial resolutions. The proposed method can also be used with directional data derived from other techniques than dMRI, which will facilitate further validation of the existence of sheet structure.

Sheet Probability Index (SPI): Characterizing the geometrical organization of the white matter with diffusion MRI.

The question whether our brain pathways adhere to a geometric grid structure has been a popular topic of debate in the diffusion imaging and neuroscience societies. Wedeen et al. (2012a, b) proposed that the brain's white matter is organized like parallel sheets of interwoven pathways. Catani et al. (2012) concluded that this grid pattern is most likely an artifact, resulting from methodological biases that cause the tractography pathways to cross in orthogonal angles. To date, ambiguities in the mathematical conditions for a sheet structure to exist (e.g. its relation to orthogonal angles) combined with the lack of extensive quantitative evidence have prevented wide acceptance of the hypothesis. In this work, we formalize the relevant terminology and recapitulate the condition for a sheet structure to exist. Note that this condition is not related to the presence or absence of orthogonal crossing fibers, and that sheet structure is defined formally as a surface formed by two sets of interwoven pathways intersecting at arbitrary angles within the surface. To quantify the existence of sheet structure, we present a novel framework to compute the sheet probability index (SPI), which reflects the presence of sheet structure in discrete orientation data (e.g. fiber peaks derived from diffusion MRI). With simulation experiments we investigate the effect of spatial resolution, curvature of the fiber pathways, and measurement noise on the ability to detect sheet structure. In real diffusion MRI data experiments we can identify various regions where the data supports sheet structure (high SPI values), but also areas where the data does not support sheet structure (low SPI values) or where no reliable conclusion can be drawn. Several areas with high SPI values were found to be consistent across subjects, across multiple data sets obtained with different scanners, resolutions, and degrees of diffusion weighting, and across various modeling techniques. Under the strong assumption that the diffusion MRI peaks reflect true axons, our results would therefore indicate that pathways do not form sheet structures at every crossing fiber region but instead at well-defined locations in the brain. With this framework, sheet structure location, extent, and orientation could potentially serve as new structural features of brain tissue. The proposed method can be extended to quantify sheet structure in directional data obtained with techniques other than diffusion MRI, which is essential for further validation.

Functional imaging of murine hearts using accelerated self-gated UTE cine MRI.

We introduce a fast protocol for ultra-short echo time (UTE) Cine magnetic resonance imaging (MRI) of the beating murine heart. The sequence involves a self-gated UTE with golden-angle radial acquisition and compressed sensing reconstruction. The self-gated acquisition is performed asynchronously with the heartbeat, resulting in a randomly undersampled kt-space that facilitates compressed sensing reconstruction. The sequence was tested in 4 healthy rats and 4 rats with chronic myocardial infarction, approximately 2 months after surgery. As a control, a non-accelerated self-gated multi-slice FLASH sequence with an echo time (TE) of 2.76 ms, 4.5 signal averages, a matrix of 192 × 192, and an acquisition time of 2 min 34 s per slice was used to obtain Cine MRI with 15 frames per heartbeat. Non-accelerated UTE MRI was performed with TE = 0.29 ms, a reconstruction matrix of 192 × 192, and an acquisition time of 3 min 47 s per slice for 3.5 averages. Accelerated imaging with 2×, 4× and 5× undersampled kt-space data was performed with 1 min, 30 and 15 s acquisitions, respectively. UTE Cine images up to 5× undersampled kt-space data could be successfully reconstructed using a compressed sensing algorithm. In contrast to the FLASH Cine images, flow artifacts in the UTE images were nearly absent due to the short echo time, simplifying segmentation of the left ventricular (LV) lumen. LV functional parameters derived from the control and the accelerated Cine movies were statistically identical.

Accelerated high-frame-rate mouse heart cine-MRI using compressed sensing reconstruction.

We introduce a new protocol to obtain very high-frame-rate cinematographic (Cine) MRI movies of the beating mouse heart within a reasonable measurement time. The method is based on a self-gated accelerated fast low-angle shot (FLASH) acquisition and compressed sensing reconstruction. Key to our approach is that we exploit the stochastic nature of the retrospective triggering acquisition scheme to produce an undersampled and random k-t space filling that allows for compressed sensing reconstruction and acceleration. As a standard, a self-gated FLASH sequence with a total acquisition time of 10 min was used to produce single-slice Cine movies of seven mouse hearts with 90 frames per cardiac cycle. Two times (2×) and three times (3×) k-t space undersampled Cine movies were produced from 2.5- and 1.5-min data acquisitions, respectively. The accelerated 90-frame Cine movies of mouse hearts were successfully reconstructed with a compressed sensing algorithm. The movies had high image quality and the undersampling artifacts were effectively removed. Left ventricular functional parameters, i.e. end-systolic and end-diastolic lumen surface areas and early-to-late filling rate ratio as a parameter to evaluate diastolic function, derived from the standard and accelerated Cine movies, were nearly identical.

A new methodology for multiscale myocardial deformation and strain analysis based on tagging MRI.

Myocardial deformation and strain can be investigated using suitably encoded cine MRI that admits disambiguation of material motion. Practical limitations currently restrict the analysis to in-plane motion in cross-sections of the heart (2D + time), but the proposed method readily generalizes to 3D + time. We propose a new, promising methodology, which departs from a multiscale algorithm that exploits local scale selection so as to obtain a robust estimate for the velocity gradient tensor field. Time evolution of the deformation tensor is governed by a first-order ordinary differential equation, which is completely determined by this velocity gradient tensor field. We solve this matrix-ODE analytically and present results obtained from healthy volunteers as well as from patient data. The proposed method requires only off-the-shelf algorithms and is readily applicable to planar or volumetric tagging MRI sampled on arbitrary coordinate grids.

Measures for pathway analysis in brain white matter using diffusion tensor images.

In this paper we discuss new measures for connectivity analysis of brain white matter, using MR diffusion tensor imaging. Our approach is based on Riemannian geometry, the viability of which has been demonstrated by various researchers in foregoing work. In the Riemannian framework bundles of axons are represented by geodesics on the manifold. Here we do not discuss methods to compute these geodesics, nor do we rely on the availability of geodesics. Instead we propose local measures which are directly computable from the local DTI data, and which enable us to preselect viable or exclude uninteresting seed points for the potentially time consuming extraction of geodesics. If geodesics are available, our measures can be readily applied to these as well. We consider two types of geodesic measures. One pertains to the connectivity saliency of a geodesic, the second to its stability with respect to local spatial perturbations. For the first type of measure we consider both differential as well as integral measures for characterizing a geodesic's saliency either locally or globally. (In the latter case one needs to be in possession of the geodesic curve, in the former case a single tangent vector suffices.) The second type of measure is intrinsically local, and turns out to be related to a well known tensor in Riemannian geometry.

The hierarchical structure of images.

Using a Gaussian scale space, one can use the extra dimension, viz. scale, for investigation of "built-in" properties of the image in scale space. We show that one of such induced properties is the nesting of special iso-intensity manifolds, which yield an implicitly present hierarchy of the critical points and regions of their influence, in the original image. Its very nature allows one not only to segment the original image automatically, but also to apply "logical filters" to it, obtaining simplified images. We give an algorithm deriving this hierarchy and show its effectiveness on two different kinds of images, both with respect to segmentation and simplification.