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White matter microstructure underpins cognition and function in the human brain through the facilitation of neuronal communication, and the non-invasive characterization of this structure remains a research frontier in the neuroscience community. Efforts to assess white matter microstructure, however, are hampered by the sheer amount of information needed for characterization. Current techniques within neuroimaging deal with this problem by representing white matter features with single scalars that are often not easy to interpret. Here, we address these issues by introducing tools from materials science for the characterization of white matter microstructure. We investigate structure on a mesoscopic scale by analyzing its homogeneity and determining which regions of the brain are structurally homogeneous, or "crystalline" in the context of materials science. We find that crystallinity provides novel information and varies across the brain along interpretable lines of anatomical difference, with highest homogeneity in regions adjacent to the corpus callosum. Furthermore, crystallinity is highly reliable, and yet also varies between individuals, making it a potentially useful biomarker to examine individual differences in white matter along various dimensions. We also parcellate white matter into "crystal grains," or contiguous sets of voxels of high structural similarity, and find overlap with other white matter parcellations. Finally, we characterize the shapes of local white matter signatures through another tool from materials science - bond-orientational order parameters - and locate fiber crossings and fascicles with this new technique. Our results provide new means of assessing white matter microstructure on multiple length scales, and open new avenues of future inquiry. We hope that this work fosters future productive dialogue between the fields of soft matter and neuroscience.

The psychosis spectrum is associated with structural dysconnectivity concentrated in transmodal association cortex. However, understanding of this pathophysiology has been limited by an exclusive focus on the direct connections to a region. Using Network Control Theory, we measured variation in both direct and indirect structural connections to a region to gain new insights into the pathophysiology of the psychosis spectrum. We used psychosis symptom data and structural connectivity in 1,068 youths aged 8 to 22 years from the Philadelphia Neurodevelopmental Cohort. Applying a Network Control Theory metric called average controllability, we estimated each brain region's capacity to leverage its direct and indirect structural connections to control linear brain dynamics. Next, using non-linear regression, we determined the accuracy with which average controllability could predict negative and positive psychosis spectrum symptoms in out-of-sample testing. We also compared prediction performance for average controllability versus strength, which indexes only direct connections to a region. Finally, we assessed how the prediction performance for psychosis spectrum symptoms varied over the functional hierarchy spanning unimodal to transmodal cortex. Average controllability outperformed strength at predicting positive psychosis spectrum symptoms, demonstrating that indexing indirect structural connections to a region improved prediction performance. Critically, improved prediction was concentrated in association cortex for average controllability, whereas prediction performance for strength was uniform across the cortex, suggesting that indexing indirect connections is crucial in association cortex. Examining inter-individual variation in direct and indirect structural connections to association cortex is crucial for accurate prediction of positive psychosis spectrum symptoms.

We present a method to discover differences between populations with respect to the spatial coherence of their oriented white matter microstructure in arbitrarily shaped white matter regions. This method is applied to diffusion MRI scans of a subset of the Human Connectome Project dataset: 57 pairs of monozygotic and 52 pairs of dizygotic twins. After controlling for morphological similarity between twins, we identify 3.7% of all white matter as being associated with genetic similarity (35.1k voxels, $p < 10^{-4}$, false discovery rate 1.5%), 75% of which spatially clusters into twenty-two contiguous white matter regions. Furthermore, we show that the orientation similarity within these regions generalizes to a subset of 47 pairs of non-twin siblings, and show that these siblings are on average as similar as dizygotic twins. The regions are located in deep white matter including the superior longitudinal fasciculus, the optic radiations, the middle cerebellar peduncle, the corticospinal tract, and within the anterior temporal lobe, as well as the cerebellum, brain stem, and amygdalae. These results extend previous work using undirected fractional anisotrophy for measuring putative heritable influences in white matter. Our multidirectional extension better accounts for crossing fiber connections within voxels. This bottom up approach has at its basis a novel measurement of coherence within neighboring voxel dyads between subjects, and avoids some of the fundamental ambiguities encountered with tractographic approaches to white matter analysis that estimate global connectivity.

White matter structures composed of myelinated axons in the living human brain are primarily studied by diffusion-weighted MRI (dMRI). These long-range projections are typically characterized in a two-step process: dMRI is used to estimate the orientation of axons within each voxel, then these local orientations are linked together to estimate the spatial extent of putative white matter bundles. Tractography, the process of tracing bundles across voxels, either requires computationally expensive (probabilistic) simulations to model uncertainty in fiber orientation or ignores it completely (deterministic). Probabilistic simulation necessarily generates a finite number of trajectories, introducing "simulation error" to trajectory estimates. Here we introduce a method to analytically (via a closed-form solution) take an orientation distribution function (ODF) from each voxel and calculate the probabilities that a trajectory projects from a voxel into each directly adjacent voxel. We validate our method by demonstrating that probabilistic simulations converge to our analytically computed probabilities at the voxel level as the number of simulated seeds increases. We show that our method accurately calculates the ground-truth transition probabilities from a phantom dataset. As a demonstration, we incoroporate our analytic method for voxel transition probabilities into the Voxel Graph framework, creating a quantitative framework for assessing white matter structure that we call "analytic tractography". The long-range connectivity problem is reduced to finding paths in a graph whose adjacency structure reflects voxel-to-voxel analytic transition probabilities. We demonstrate this approach performs comparably to many current probabilistic and deterministic approaches at a fraction of the computational cost. Open source software software is provided.

This paper advocates Riemannian multi-manifold modeling in the context of network-wide non-stationary time-series analysis. Time-series data, collected sequentially over time and across a network, yield features which are viewed as points in or close to a union of multiple submanifolds of a Riemannian manifold, and distinguishing disparate time series amounts to clustering multiple Riemannian submanifolds. To support the claim that exploiting the latent Riemannian geometry behind many statistical features of time series is beneficial to learning from network data, this paper focuses on brain networks and puts forth two feature-generation schemes for network-wide dynamic time series. The first is motivated by Granger-causality arguments and uses an auto-regressive moving average model to map low-rank linear vector subspaces, spanned by column vectors of appropriately defined observability matrices, to points into the Grassmann manifold. The second utilizes (non-linear) dependencies among network nodes by introducing kernel-based partial correlations to generate points in the manifold of positive-definite matrices. Capitilizing on recently developed research on clustering Riemannian submanifolds, an algorithm is provided for distinguishing time series based on their geometrical properties, revealed within Riemannian feature spaces. Extensive numerical tests demonstrate that the proposed framework outperforms classical and state-of-the-art techniques in clustering brain-network states/structures hidden beneath synthetic fMRI time series and brain-activity signals generated from real brain-network structural connectivity matrices.

A critical mystery in neuroscience lies in determining how anatomical structure impacts the complex functional dynamics of human thought. How does large-scale brain circuitry constrain states of neuronal activity and transitions between those states? We address these questions using a maximum entropy model of brain dynamics informed by white matter tractography. We demonstrate that the most probable brain states -- characterized by minimal energy -- display common activation profiles across brain areas: local spatially-contiguous sets of brain regions reminiscent of cognitive systems are co-activated frequently. The predicted activation rate of these systems is highly correlated with the observed activation rate measured in a separate resting state fMRI data set, validating the utility of the maximum entropy model in describing neurophysiologial dynamics. This approach also offers a formal notion of the energy of activity within a system, and the energy of activity shared between systems. We observe that within- and between-system energies cleanly separate cognitive systems into distinct categories, optimized for differential contributions to integrated v.s. segregated function. These results support the notion that energetic and structural constraints circumscribe brain dynamics, offering novel insights into the roles that cognitive systems play in driving whole-brain activation patterns.

The complexity of neural dynamics stems in part from the complexity of the underlying anatomy. Yet how the organization of white matter architecture constrains how the brain transitions from one cognitive state to another remains unknown. Here we address this question from a computational perspective by defining a brain state as a pattern of activity across brain regions. Drawing on recent advances in network control theory, we model the underlying mechanisms of brain state transitions as elicited by the collective control of region sets. Specifically, we examine how the brain moves from a specified initial state (characterized by high activity in the default mode) to a specified target state (characterized by high activity in primary sensorimotor cortex) in finite time. Across all state transitions, we observe that the supramarginal gyrus and the inferior parietal lobule consistently acted as efficient, low energy control hubs, consistent with their strong anatomical connections to key input areas of sensorimotor cortex. Importantly, both these and other regions in the fronto-parietal, cingulo-opercular, and attention systems are poised to affect a broad array of state transitions that cannot easily be classified by traditional notions of control common in the engineering literature. This theoretical versatility comes with a vulnerability to injury. In patients with mild traumatic brain injury, we observe a loss of specificity in putative control processes, suggesting greater susceptibility to damage-induced noise in neurophysiological activity. These results offer fundamentally new insights into the mechanisms driving brain state transitions in healthy cognition and their alteration following injury.

The ability to modulate brain states using targeted stimulation is increasingly being employed to treat neurological disorders and to enhance human performance. Despite the growing interest in brain stimulation as a form of neuromodulation, much remains unknown about the network-level impact of these focal perturbations. To study the system wide impact of regional stimulation, we employ a data-driven computational model of nonlinear brain dynamics to systematically explore the effects of targeted stimulation. Validating predictions from network control theory, we uncover the relationship between regional controllability and the focal versus global impact of stimulation, and we relate these findings to differences in the underlying network architecture. Finally, by mapping brain regions to cognitive systems, we observe that the default mode system imparts large global change despite being highly constrained by structural connectivity. This work forms an important step towards the development of personalized stimulation protocols for medical treatment or performance enhancement., Comment: 54 pages, 10 figures, includes Supplementary Information

Cognitive function is driven by dynamic interactions between large-scale neural circuits or networks, enabling behavior. Fundamental principles constraining these dynamic network processes have remained elusive. Here we use network control theory to offer a mechanistic explanation for how the brain moves between cognitive states drawn from the network organization of white matter microstructure. Our results suggest that densely connected areas, particularly in the default mode system, facilitate the movement of the brain to many easily-reachable states. Weakly connected areas, particularly in cognitive control systems, facilitate the movement of the brain to difficult-to-reach states. Areas located on the boundary between network communities, particularly in attentional control systems, facilitate the integration or segregation of diverse cognitive systems. Our results suggest that structural network differences between the cognitive circuits dictate their distinct roles in controlling dynamic trajectories of brain network function., Comment: 14 pages, 4 figures, supplementary materials

Information mapping is a popular application of Multivoxel Pattern Analysis (MVPA) to fMRI. Information maps are constructed using the so called searchlight method, where the spherical multivoxel neighborhood of every voxel (i.e., a searchlight) in the brain is evaluated for the presence of task-relevant response patterns. Despite their widespread use, information maps present several challenges for interpretation. One such challenge has to do with inferring the size and shape of a multivoxel pattern from its signature on the information map. To address this issue, we formally examined the geometric basis of this mapping relationship. Based on geometric considerations, we show how and why small patterns (i.e., having smaller spatial extents) can produce a larger signature on the information map as compared to large patterns, independent of the size of the searchlight radius. Furthermore, we show that the number of informative searchlights over the brain increase as a function of searchlight radius, even in the complete absence of any multivariate response patterns. These properties are unrelated to the statistical capabilities of the pattern-analysis algorithms used but are obligatory geometric properties arising from using the searchlight procedure., Comment: 15 pages, 7 figures