Predicting Language Function Post-Stroke: A Model-Based Structural Connectivity Approach.

BACKGROUND: The prediction of post-stroke language function is essential for the development of individualized treatment plans based on the personal recovery potential of aphasic stroke patients. OBJECTIVE: To establish a framework for integrating information on connectivity disruption of the language network based on routinely collected clinical magnetic resonance (MR) images into Random Forest modeling to predict post-stroke language function. METHODS: Language function was assessed in 76 stroke patients from the Non-Invasive Repeated Therapeutic Stimulation for Aphasia Recovery trial, using the Token Test (TT), Boston Naming Test (BNT), and Semantic Verbal Fluency (sVF) Test as primary outcome measures. Individual infarct masks were superimposed onto a diffusion tensor imaging tractogram reference set to calculate Change in Connectivity scores of language-relevant gray matter regions as estimates of structural connectivity disruption. Multivariable Random Forest models were derived to predict language function. RESULTS: Random Forest models explained moderate to high amount of variance at baseline and follow-up for the TT (62.7% and 76.2%), BNT (47.0% and 84.3%), and sVF (52.2% and 61.1%). Initial language function and non-verbal cognitive ability were the most important variables to predict language function. Connectivity disruption explained additional variance, resulting in a prediction error increase of up to 12.8% with variable omission. Left middle temporal gyrus (12.8%) and supramarginal gyrus (9.8%) were identified as among the most important network nodes. CONCLUSION: Connectivity disruption of the language network adds predictive value beyond lesion volume, initial language function, and non-verbal cognitive ability. Obtaining information on connectivity disruption based on routine clinical MR images constitutes a significant advancement toward practical clinical application.

Release the Krakencoder: A unified brain connectome translation and fusion tool.

Brain connectivity can be estimated in many ways, depending on modality and processing strategy. Here we present the Krakencoder, a joint connectome mapping tool that simultaneously, bidirectionally translates between structural (SC) and functional connectivity (FC), and across different atlases and processing choices via a common latent representation. These mappings demonstrate unprecedented accuracy and individual-level identifiability; the mapping between SC and FC has identifiability 42-54% higher than existing models. The Krakencoder combines all connectome flavors via a shared low-dimensional latent space. This "fusion" representation i) better reflects familial relatedness, ii) preserves age- and sex-relevant information and iii) enhances cognition-relevant information. The Krakencoder can be applied without retraining to new, out-of-age-distribution data while still preserving inter-individual differences in the connectome predictions and familial relationships in the latent representations. The Krakencoder is a significant leap forward in capturing the relationship between multi-modal brain connectomes in an individualized, behaviorally- and demographically-relevant way.

The sequence of regional structural disconnectivity due to multiple sclerosis lesions.

Prediction of disease progression is challenging in multiple sclerosis as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in multiple sclerosis. In a full cohort of 482 multiple sclerosis patients (age: 41.83 ± 11.63 years, 71.57% females), the Expanded Disability Status Scale was used to classify patients into (i) no or mild (Expanded Disability Status Scale <3) versus (ii) moderate or severe disability groups (Expanded Disability Status Scale ≥3). In 363 out of 482 patients, quantitative susceptibility mapping was used to identify paramagnetic rim lesions, which are maintained by a rim of iron-laden innate immune cells. In 171 out of 482 patients, Brief International Cognitive Assessment was used to identify subjects as being cognitively preserved or impaired. Network Modification Tool was used to estimate the regional structural disconnectivity due to multiple sclerosis lesions. Discriminative event-based modelling was applied to investigate the sequence of regional structural disconnectivity due to (i) all representative T2 fluid-attenuated inversion recovery lesions, (ii) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across disability groups ('no to mild disability' to 'moderate to severe disability'), (iii) all representative T2 fluid-attenuated inversion recovery lesions and (iv) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across cognitive status ('cognitively preserved' to 'cognitively impaired'). In the full cohort, structural disconnection in the ventral attention and subcortical networks, particularly in the supramarginal and putamen regions, was an early biomarker of moderate or severe disability. The earliest biomarkers of disability progression were structural disconnections due to paramagnetic rim lesions in the motor-related regions. Subcortical structural disconnection, particularly in the ventral diencephalon and thalamus regions, was an early biomarker of cognitive impairment. Our data-driven model revealed that the structural disconnection in the subcortical regions, particularly in the thalamus, is an early biomarker for both disability and cognitive impairment in multiple sclerosis. Paramagnetic rim lesions-related structural disconnection in the motor cortex may identify the patients at risk for moderate or severe disability in multiple sclerosis. Such information might be used to identify people with multiple sclerosis who have an increased risk of disability progression or cognitive decline in order to provide personalized treatment plans.

Data-driven biomarkers outperform theory-based biomarkers in predicting stroke motor outcomes.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have predicted motor outcomes based on the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to predict chronic motor outcomes after stroke and compares the accuracy of these predictions to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients (293 female/496 male) from the ENIGMA Stroke Recovery Working Group (age 64.9±18.0 years; time since stroke 12.2±0.2 months; normalised motor score 0.7±0.5 (range [0,1]). The out-of-sample prediction accuracy of two theory-based biomarkers was assessed: lesion load of the corticospinal tract, and lesion load of multiple descending motor tracts. These theory-based prediction accuracies were compared to the prediction accuracy from three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had better prediction accuracy - as measured by higher explained variance in chronic motor outcomes - than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, p < 0.001), performing significantly better than predictions using the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, p< 0.001) and of multiple descending motor tracts (R2 = 0.180, p < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 =0.200, p < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 =0.167, p < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved prediction accuracy for theory-based and data-driven biomarkers. Finally, combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, p < 0.001. Overall, these results demonstrate that models that predict chronic motor outcomes using data-driven features, particularly when lesion data is represented in terms of structural disconnection, perform better than models that predict chronic motor outcomes using theory-based features from the motor system. However, combining both theory-based and data-driven models provides the best predictions.

Frontoparietal network activation is associated with motor recovery in ischemic stroke patients.

Strokes cause lesions that damage brain tissue, disrupt normal brain activity patterns and can lead to impairments in motor function. Although modulation of cortical activity is central to stimulation-based rehabilitative therapies, aberrant and adaptive patterns of brain activity after stroke have not yet been fully characterized. Here, we apply a brain dynamics analysis approach to study longitudinal brain activity patterns in individuals with ischemic pontine stroke. We first found 4 commonly occurring brain states largely characterized by high amplitude activations in the visual, frontoparietal, default mode, and motor networks. Stroke subjects spent less time in the frontoparietal state compared to controls. For individuals with dominant-hand CST damage, more time spent in the frontoparietal state from 1 week to 3-6 months post-stroke was associated with better motor recovery over the same time period, an association which was independent of baseline impairment. Furthermore, the amount of time spent in brain states was linked empirically to functional connectivity. This work suggests that when the dominant-hand CST is compromised in stroke, resting state configurations may include increased activation of the frontoparietal network, which may facilitate compensatory neural pathways that support recovery of motor function when traditional motor circuits of the dominant-hemisphere are compromised.

Shared functional connections within and between cortical networks predict cognitive abilities in adult males and females.

A thorough understanding of sex-independent and sex-specific neurobiological features that underlie cognitive abilities in healthy individuals is essential for the study of neurological illnesses in which males and females differentially experience and exhibit cognitive impairment. Here, we evaluate sex-independent and sex-specific relationships between functional connectivity and individual cognitive abilities in 392 healthy young adults (196 males) from the Human Connectome Project. First, we establish that sex-independent models comparably predict crystallised abilities in males and females, but only successfully predict fluid abilities in males. Second, we demonstrate sex-specific models comparably predict crystallised abilities within and between sexes, and generally fail to predict fluid abilities in either sex. Third, we reveal that largely overlapping connections between visual, dorsal attention, ventral attention, and temporal parietal networks are associated with better performance on crystallised and fluid cognitive tests in males and females, while connections within visual, somatomotor, and temporal parietal networks are associated with poorer performance. Together, our findings suggest that shared neurobiological features of the functional connectome underlie crystallised and fluid abilities across the sexes.

Functional connectome reorganization relates to post-stroke motor recovery and structural and functional disconnection.

Motor recovery following ischemic stroke is contingent on the ability of surviving brain networks to compensate for damaged tissue. In rodent models, sensory and motor cortical representations have been shown to remap onto intact tissue around the lesion site, but remapping to more distal sites (e.g. in the contralesional hemisphere) has also been observed. Resting state functional connectivity (FC) analysis has been employed to study compensatory network adaptations in humans, but mechanisms and time course of motor recovery are not well understood. Here, we examine longitudinal FC in 23 first-episode ischemic pontine stroke patients and utilize a graph matching approach to identify patterns of functional connectivity reorganization during recovery. We quantified functional reorganization between several intervals ranging from 1 week to 6 months following stroke, and demonstrated that the areas that undergo functional reorganization most frequently are in cerebellar/subcortical networks. Brain regions with more structural and functional connectome disruption due to the stroke also had more remapping over time. Finally, we show that functional reorganization is correlated with the extent of motor recovery in the early to late subacute phases, and furthermore, individuals with greater baseline motor impairment demonstrate more extensive early subacute functional reorganization (from one to two weeks post-stroke) and this reorganization correlates with better motor recovery at 6 months. Taken together, these results suggest that our graph matching approach can quantify recovery-relevant, whole-brain functional connectivity network reorganization after stroke.

Distinct functional and structural connections predict crystallised and fluid cognition in healthy adults.

White matter pathways between neurons facilitate neuronal coactivation patterns in the brain. Insight into how these structural and functional connections underlie complex cognitive functions provides an important foundation with which to delineate disease-related changes in cognitive functioning. Here, we integrate neuroimaging, connectomics, and machine learning approaches to explore how functional and structural brain connectivity relate to cognition. Specifically, we evaluate the extent to which functional and structural connectivity predict individual crystallised and fluid cognitive abilities in 415 unrelated healthy young adults (202 females) from the Human Connectome Project. We report three main findings. First, we demonstrate functional connectivity is more predictive of cognitive scores than structural connectivity, and, furthermore, integrating the two modalities does not increase explained variance. Second, we show the quality of cognitive prediction from connectome measures is influenced by the choice of grey matter parcellation, and, possibly, how that parcellation is derived. Third, we find that distinct functional and structural connections predict crystallised and fluid abilities. Taken together, our results suggest that functional and structural connectivity have unique relationships with crystallised and fluid cognition and, furthermore, studying both modalities provides a more comprehensive insight into the neural correlates of cognition.

A temporal decomposition method for identifying venous effects in task-based fMRI.

The spatial resolution of functional magnetic resonance imaging (fMRI) is fundamentally limited by effects from large draining veins. Here we describe an analysis method that provides data-driven estimates of these effects in task-based fMRI. The method involves fitting a one-dimensional manifold that characterizes variation in response timecourses observed in a given dataset, and then using identified early and late timecourses as basis functions for decomposing responses into components related to the microvasculature (capillaries and small venules) and the macrovasculature (large veins), respectively. We show the removal of late components substantially reduces the superficial cortical depth bias of fMRI responses and helps eliminate artifacts in cortical activity maps. This method provides insight into the origins of the fMRI signal and can be used to improve the spatial accuracy of fMRI.

Sex classification using long-range temporal dependence of resting-state functional MRI time series.

A thorough understanding of sex differences that exist in the brains of healthy individuals is crucial for the study of neurological illnesses that exhibit phenotypic differences between males and females. Here we evaluate sex differences in regional temporal dependence of resting-state brain activity in 195 adult male-female pairs strictly matched for total grey matter volume from the Human Connectome Project. We find that males have more persistent temporal dependence in regions within temporal, parietal, and occipital cortices. Machine learning algorithms trained on regional temporal dependence measures achieve sex classification accuracies up to 81%. Regions with the strongest feature importance in the sex classification task included cerebellum, amygdala, and frontal and occipital cortices. Secondarily, we show that even after strict matching of total gray matter volume, significant volumetric sex differences persist; males have larger absolute cerebella, hippocampi, parahippocampi, thalami, caudates, and amygdalae while females have larger absolute cingulates, precunei, and frontal and parietal cortices. Sex classification based on regional volume achieves accuracies up to 85%, highlighting the importance of strict volume-matching when studying brain-based sex differences. Differential patterns in regional temporal dependence between the sexes identifies a potential neurobiological substrate or environmental effect underlying sex differences in functional brain activation patterns.

Ultra-high-resolution fMRI of Human Ventral Temporal Cortex Reveals Differential Representation of Categories and Domains.

Human ventral temporal cortex (VTC) is critical for visual recognition. It is thought that this ability is supported by large-scale patterns of activity across VTC that contain information about visual categories. However, it is unknown how category representations in VTC are organized at the submillimeter scale and across cortical depths. To fill this gap in knowledge, we measured BOLD responses in medial and lateral VTC to images spanning 10 categories from five domains (written characters, bodies, faces, places, and objects) at an ultra-high spatial resolution of 0.8 mm using 7 Tesla fMRI in both male and female participants. Representations in lateral VTC were organized most strongly at the general level of domains (e.g., places), whereas medial VTC was also organized at the level of specific categories (e.g., corridors and houses within the domain of places). In both lateral and medial VTC, domain-level and category-level structure decreased with cortical depth, and downsampling our data to standard resolution (2.4 mm) did not reverse differences in representations between lateral and medial VTC. The functional diversity of representations across VTC partitions may allow downstream regions to read out information in a flexible manner according to task demands. These results bridge an important gap between electrophysiological recordings in single neurons at the micron scale in nonhuman primates and standard-resolution fMRI in humans by elucidating distributed responses at the submillimeter scale with ultra-high-resolution fMRI in humans.SIGNIFICANCE STATEMENT Visual recognition is a fundamental ability supported by human ventral temporal cortex (VTC). However, the nature of fine-scale, submillimeter distributed representations in VTC is unknown. Using ultra-high-resolution fMRI of human VTC, we found differential distributed visual representations across lateral and medial VTC. Domain representations (e.g., faces, bodies, places, characters) were most salient in lateral VTC, whereas category representations (e.g., corridors/houses within the domain of places) were equally salient in medial VTC. These results bridge an important gap between electrophysiological recordings in single neurons at a micron scale and fMRI measurements at a millimeter scale.

Longitudinal increases in structural connectome segregation and functional connectome integration are associated with better recovery after mild TBI.

Traumatic brain injury damages white matter pathways that connect brain regions, disrupting transmission of electrochemical signals and causing cognitive and emotional dysfunction. Connectome-level mechanisms for how the brain compensates for injury have not been fully characterized. Here, we collected serial MRI-based structural and functional connectome metrics and neuropsychological scores in 26 mild traumatic brain injury subjects (29.4 ± 8.0 years, 20 males) at 1 and 6 months postinjury. We quantified the relationship between functional and structural connectomes using network diffusion (ND) model propagation time, a measure that can be interpreted as how much of the structural connectome is being utilized for the spread of functional activation, as captured via the functional connectome. Overall cognition showed significant improvement from 1 to 6 months (t25 = -2.15, p = .04). None of the structural or functional global connectome metrics was significantly different between 1 and 6 months, or when compared to 34 age- and gender-matched controls (28.6 ± 8.8 years, 25 males). We predicted longitudinal changes in overall cognition from changes in global connectome measures using a partial least squares regression model (cross-validated R2 = .27). We observe that increased ND model propagation time, increased structural connectome segregation, and increased functional connectome integration were related to better cognitive recovery. We interpret these findings as suggesting two connectome-based postinjury recovery mechanisms: one of neuroplasticity that increases functional connectome integration and one of remote white matter degeneration that increases structural connectome segregation. We hypothesize that our inherently multimodal measure of ND model propagation time captures the interplay between these two mechanisms.

A critical assessment of data quality and venous effects in sub-millimeter fMRI.

Advances in hardware, pulse sequences, and reconstruction techniques have made it possible to perform functional magnetic resonance imaging (fMRI) at sub-millimeter resolution while maintaining high spatial coverage and acceptable signal-to-noise ratio. Here, we examine whether sub-millimeter fMRI can be used as a routine method for obtaining accurate measurements of fine-scale local neural activity. We conducted fMRI in human visual cortex during a simple event-related visual experiment (7 T, gradient-echo EPI, 0.8-mm isotropic voxels, 2.2-s sampling rate, 84 slices), and developed analysis and visualization tools to assess the quality of the data. Our results fall along three lines of inquiry. First, we find that the acquired fMRI images, combined with appropriate surface-based processing, provide reliable and accurate measurements of fine-scale blood oxygenation level dependent (BOLD) activity patterns. Second, we show that the highly folded structure of cortex causes substantial biases on spatial resolution and data visualization. Third, we examine the well-recognized issue of venous contributions to fMRI signals. In a systematic assessment of large sections of cortex measured at a fine scale, we show that time-averaged T2*-weighted EPI intensity is a simple, robust marker of venous effects. These venous effects are unevenly distributed across cortex, are more pronounced in gyri and outer cortical depths, and are, to a certain degree, in consistent locations across subjects relative to cortical folding. Furthermore, we show that these venous effects are strongly correlated with BOLD responses evoked by the experiment. We conclude that sub-millimeter fMRI can provide robust information about fine-scale BOLD activity patterns, but special care must be exercised in visualizing and interpreting these patterns, especially with regards to the confounding influence of the brain's vasculature. To help translate these methodological findings to neuroscience research, we provide practical suggestions for both high-resolution and standard-resolution fMRI studies.

The Human Connectome Project 7 Tesla retinotopy dataset: Description and population receptive field analysis.

About a quarter of human cerebral cortex is dedicated mainly to visual processing. The large-scale spatial organization of visual cortex can be measured with functional magnetic resonance imaging (fMRI) while subjects view spatially modulated visual stimuli, also known as "retinotopic mapping." One of the datasets collected by the Human Connectome Project involved ultrahigh-field (7 Tesla) fMRI retinotopic mapping in 181 healthy young adults (1.6-mm resolution), yielding the largest freely available collection of retinotopy data. Here, we describe the experimental paradigm and the results of model-based analysis of the fMRI data. These results provide estimates of population receptive field position and size. Our analyses include both results from individual subjects as well as results obtained by averaging fMRI time series across subjects at each cortical and subcortical location and then fitting models. Both the group-average and individual-subject results reveal robust signals across much of the brain, including occipital, temporal, parietal, and frontal cortex as well as subcortical areas. The group-average results agree well with previously published parcellations of visual areas. In addition, split-half analyses show strong within-subject reliability, further demonstrating the high quality of the data. We make publicly available the analysis results for individual subjects and the group average, as well as associated stimuli and analysis code. These resources provide an opportunity for studying fine-scale individual variability in cortical and subcortical organization and the properties of high-resolution fMRI. In addition, they provide a set of observations that can be compared with other Human Connectome Project measures acquired in these same participants.

Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+ healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

Deactivation in the posterior mid-cingulate cortex reflects perceptual transitions during binocular rivalry: Evidence from simultaneous EEG-fMRI.

Binocular rivalry is a phenomenon in which perception spontaneously shifts between two different images that are dichoptically presented to the viewer. By elucidating the cortical networks responsible for these stochastic fluctuations in perception, we can potentially learn much about the neural correlates of visual awareness. We obtained concurrent EEG-fMRI data for a group of 20 healthy human subjects during the continuous presentation of dichoptic visual stimuli. The two eyes' images were tagged with different temporal frequencies so that eye specific steady-state visual evoked potential (SSVEP) signals could be extracted from the EEG data for direct comparison with changes in fMRI BOLD activity associated with binocular rivalry. We additionally included a smooth replay condition that emulated the perceptual transitions experienced during binocular rivalry as a control stimulus. We evaluated a novel SSVEP-informed fMRI analysis in this study in order to delineate the temporal dynamics of rivalry-related BOLD activity from both an electrophysiological and behavioral perspective. In this manner, we assessed BOLD activity during rivalry that was directly correlated with peaks and crosses of the two rivaling, frequency-tagged SSVEP signals, for comparison with BOLD activity associated with subject reported perceptual transitions. Our findings point to a critical role of a right lateralized fronto-parietal network in the processing of bistable stimuli, given that BOLD activity in the right superior/inferior parietal lobules was significantly elevated throughout binocular rivalry and in particular during perceptual transitions, compared with the replay condition. Based on the SSVEP-informed analysis, rivalry was further associated with significantly enhanced BOLD suppression in the posterior mid-cingulate cortex during perceptual transitions, compared with SSVEP crosses. Overall, this work points to a careful interplay between early visual areas, the right posterior parietal cortex and the mid-cingulate cortex in mediating the spontaneous perceptual changes associated with binocular rivalry and has significant implications for future multimodal imaging studies of perception and awareness.

SSVEP signatures of binocular rivalry during simultaneous EEG and fMRI.

BACKGROUND: Binocular rivalry is a perceptual phenomenon that arises when two incompatible images are presented separately, one to each eye, and the observer experiences involuntary perceptual alternations between the two images. If the two images are flickering at two distinct frequencies, electroencephalography (EEG) can be used to track the frequency-tagged steady-state visually evoked potential (SSVEP) driven by each image as they compete for awareness, providing an objective measure of the subjective perceptual state. This spontaneous alternation in perceptual dominance is believed to be driven by neural processes across widespread regions in the brain, but the real-time mechanisms of these processes remain unclear. NEW METHOD: The goal of this study was to determine the feasibility of investigating binocular rivalry using a simultaneous EEG-fMRI approach in order to leverage the high temporal resolution of EEG with the high spatial resolution of fMRI. RESULTS: We have developed novel techniques for artifact removal and signal optimization for the rivalry-related SSVEP data collected simultaneously during fMRI. COMPARISON WITH EXISTING METHODS: Our methods address several significant technical challenges of recording SSVEP data in the noisy fMRI environment, and enabled us to successfully reconstruct SSVEP signatures of rivalry in a group of healthy human subjects. CONCLUSION: Further development and application of these techniques will enable more comprehensive integration of EEG and fMRI data collected simultaneously and could have significant implications for EEG-fMRI studies of brain activity in general.