Principles of cortical areas and their implications for neuroimaging.

Cortical organization should constrain the study of how the brain performs behavior and cognition. A fundamental concept in cortical organization is that of arealization: that the cortex is parceled into discrete areas. In part one of this report, we review how non-human animal studies have illuminated principles of cortical arealization by revealing: (1) what defines a cortical area, (2) how cortical areas are formed, (3) how cortical areas interact with one another, and (4) what "computations" or "functions" areas perform. In part two, we discuss how these principles apply to neuroimaging research. In doing so, we highlight several examples where the commonly accepted interpretation of neuroimaging observations requires assumptions that violate the principles of arealization, including nonstationary areas that move on short time scales, large-scale gradients as organizing features, and cortical areas with singular functionality that perfectly map psychological constructs. Our belief is that principles of neurobiology should strongly guide the nature of computational explanations.

Two common and distinct forms of variation in human functional brain networks.

The cortex has a characteristic layout with specialized functional areas forming distributed large-scale networks. However, substantial work shows striking variation in this organization across people, which relates to differences in behavior. While most previous work treats individual differences as linked to boundary shifts between the borders of regions, here we show that cortical 'variants' also occur at a distance from their typical position, forming ectopic intrusions. Both 'border' and 'ectopic' variants are common across individuals, but differ in their location, network associations, properties of subgroups of individuals, activations during tasks, and prediction of behavioral phenotypes. Border variants also track significantly more with shared genetics than ectopic variants, suggesting a closer link between ectopic variants and environmental influences. This work argues that these two dissociable forms of variation-border shifts and ectopic intrusions-must be separately accounted for in the analysis of individual differences in cortical systems across people.

Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice.

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Cognition and Brain System Segregation in Pediatric Brain Tumor Patients Treated with Proton Therapy.

Purpose: Pediatric brain tumor patients often experience significant cognitive sequelae. Resting-state functional MRI (rsfMRI) provides a measure of brain network organization, and we hypothesize that pediatric brain tumor patients treated with proton therapy will demonstrate abnormal brain network architecture related to cognitive outcome and radiation dosimetry. Participants and Methods: Pediatric brain tumor patients treated with proton therapy were enrolled on a prospective study of cognitive assessment using the NIH Toolbox Cognitive Domain. rsfMRI was obtained in participants able to complete unsedated MRI. Brain system segregation (BSS), a measure of brain network architecture, was calculated for the whole brain, the high-level cognition association systems, and the sensory-motor systems. Results: Twenty-six participants were enrolled in the study for cognitive assessment, and 18 completed rsfMRI. There were baseline cognitive deficits in attention and inhibition and processing speed prior to radiation with worsening performance over time in multiple domains. Average BSS across the whole brain was significantly decreased in participants compared with healthy controls (1.089 and 1.101, respectively; P = 0.001). Average segregation of association systems was significantly lower in participants than in controls (P < 0.001) while there was no difference in the sensory motor networks (P = 0.70). Right hippocampus dose was associated with worse attention and inhibition (P < 0.05) and decreased segregation in the dorsal attention network (P < 0.05). Conclusion: Higher mean dose to the right hippocampus correlated with worse dorsal attention network segregation and worse attention and inhibition cognitive performance. Patients demonstrated alterations in brain network organization of association systems measured with rsfMRI; however, somatosensory system segregation was no different from healthy children. Further work with preradiation rsfMRI is needed to assess the effects of surgery and presence of a tumor on brain network architecture.

Cognitive deficits and altered functional brain network organization in pediatric brain tumor patients.

Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Resting state functional magnetic resonance imaging allows for the study of the spontaneous fluctuations in bulk neural activity, providing insight into brain organization and function. Here, we evaluated cognitive performance and functional network architecture in pediatric brain tumor patients. Forty-nine patients (7-18 years old) with a primary brain tumor diagnosis underwent resting state imaging during regularly scheduled clinical visits. All patients were tested with a battery of cognitive assessments. Extant data from 139 typically developing children were used as controls. We found that obtaining high-quality imaging data during routine clinical scanning was feasible. Functional network organization was significantly altered in patients, with the largest disruptions observed in patients who received propofol sedation. Awake patients demonstrated significant decreases in association network segregation compared to controls. Interestingly, there was no difference in the segregation of sensorimotor networks. With a median follow-up of 3.1 years, patients demonstrated cognitive deficits in multiple domains of executive function. Finally, there was a weak correlation between decreased default mode network segregation and poor picture vocabulary score. Future work with longer follow-up, longitudinal analyses, and a larger cohort will provide further insight into this potential predictor.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

BOLD cofluctuation 'events' are predicted from static functional connectivity.

Recent work identified single time points ("events") of high regional cofluctuation in functional Magnetic Resonance Imaging (fMRI) which contain more large-scale brain network information than other, low cofluctuation time points. This suggested that events might be a discrete, temporally sparse signal which drives functional connectivity (FC) over the timeseries. However, a different, not yet explored possibility is that network information differences between time points are driven by sampling variability on a constant, static, noisy signal. Using a combination of real and simulated data, we examined the relationship between cofluctuation and network structure and asked if this relationship was unique, or if it could arise from sampling variability alone. First, we show that events are not discrete - there is a gradually increasing relationship between network structure and cofluctuation; ∼50% of samples show very strong network structure. Second, using simulations we show that this relationship is predicted from sampling variability on static FC. Finally, we show that randomly selected points can capture network structure about as well as events, largely because of their temporal spacing. Together, these results suggest that, while events exhibit particularly strong representations of static FC, there is little evidence that events are unique timepoints that drive FC structure. Instead, a parsimonious explanation for the data is that events arise from a single static, but noisy, FC structure.

Probabilistic mapping of human functional brain networks identifies regions of high group consensus.

Many recent developments surrounding the functional network organization of the human brain have focused on data that have been averaged across groups of individuals. While such group-level approaches have shed considerable light on the brain's large-scale distributed systems, they conceal individual differences in network organization, which recent work has demonstrated to be common and widespread. This individual variability produces noise in group analyses, which may average together regions that are part of different functional systems across participants, limiting interpretability. However, cost and feasibility constraints may limit the possibility for individual-level mapping within studies. Here our goal was to leverage information about individual-level brain organization to probabilistically map common functional systems and identify locations of high inter-subject consensus for use in group analyses. We probabilistically mapped 14 functional networks in multiple datasets with relatively high amounts of data. All networks show "core" (high-probability) regions, but differ from one another in the extent of their higher-variability components. These patterns replicate well across four datasets with different participants and scanning parameters. We produced a set of high-probability regions of interest (ROIs) from these probabilistic maps; these and the probabilistic maps are made publicly available, together with a tool for querying the network membership probabilities associated with any given cortical location. These quantitative estimates and public tools may allow researchers to apply information about inter-subject consensus to their own fMRI studies, improving inferences about systems and their functional specializations.

Network variants are similar between task and rest states.

Recent work has demonstrated that individual-specific variations in functional networks (termed "network variants") can be identified in individuals using resting state functional magnetic resonance imaging (fMRI). These network variants exhibit reliability over time, suggesting that they may be trait-like markers of individual differences in brain organization. However, while networks variants are reliable at rest, is is still untested whether they are stable between task and rest states. Here, we use precision data from the Midnight Scan Club (MSC) to demonstrate that (1) task data can be used to identify network variants reliably, (2) these network variants show substantial spatial overlap with those observed in rest, although state-specific effects are present, (3) network variants assign to similar canonical functional networks in task and rest states, and (4) single tasks or a combination of multiple tasks produce similar network variants to rest. Together, these findings further reinforce the trait-like nature of network variants and demonstrate the utility of using task data to define network variants.

Mapping of the Language Network With Deep Learning.

Background: Pre-surgical functional localization of eloquent cortex with task-based functional MRI (T-fMRI) is part of the current standard of care prior to resection of brain tumors. Resting state fMRI (RS-fMRI) is an alternative method currently under investigation. Here, we compare group level language localization using T-fMRI vs. RS-fMRI analyzed with 3D deep convolutional neural networks (3DCNN). Methods: We analyzed data obtained in 35 patients with brain tumors that had both language T-fMRI and RS-MRI scans during pre-surgical evaluation. The T-fMRI data were analyzed using conventional techniques. The language associated resting state network was mapped using a 3DCNN previously trained with data acquired in >2,700 normal subjects. Group level results obtained by both methods were evaluated using receiver operator characteristic analysis of probability maps of language associated regions, taking as ground truth meta-analytic maps of language T-fMRI responses generated on the Neurosynth platform. Results: Both fMRI methods localized major components of the language system (areas of Broca and Wernicke). Word-stem completion T-fMRI strongly activated Broca's area but also several task-general areas not specific to language. RS-fMRI provided a more specific representation of the language system. Conclusion: 3DCNN was able to accurately localize the language network. Additionally, 3DCNN performance was remarkably tolerant of a limited quantity of RS-fMRI data.

Human Brain Functional Network Organization Is Disrupted After Whole-Brain Radiation Therapy.

Radiation therapy (RT) plays a vital role in the treatment of brain cancers, but it frequently results in cognitive decline in the patients who receive it. Because the underlying mechanisms for this decline remain poorly understood, the brain is typically treated as a single, uniform volume when evaluating the toxic effects of RT plans. This ignorance represents a significant deficit in the field of radiation oncology, as the technology exists to manipulate dose distributions to spare regions of the brain, but there exists no body of knowledge regarding what is critical to spare. This deficit exists due to the numerous confounding factors that are frequently associated with radiotherapy, including the tumors themselves, other treatments such as surgery and chemotherapy, and dose gradients across the brain. Here, we present a case in which a 57-year-old male patient received a uniform dose of radiation across the whole brain, did not receive concurrent chemotherapy, had minimal surgical intervention and a small tumor burden, and received resting-state functional magnetic resonance imaging (fMRI) scans both before and after RT. To our knowledge, this is the first study on the effects of whole-brain radiotherapy on functional network organization, and this patient's treatment regimen represents a rare and non-replicable opportunity to isolate the effects of radiation on functional connectivity. We observed substantial changes in the subject's behavior and functional network organization over a 12-month timeframe. Interestingly, the homogenous radiation dose to the brain had a heterogeneous effect on cortical networks, and the functional networks most affected correspond with observed cognitive behavioral deficits. This novel study suggests that the cognitive decline that occurs after whole-brain radiation therapy may be network specific and related to the disruption of large-scale distributed functional systems, and it indicates that fMRI is a promising avenue of study for optimizing cognitive outcomes after RT.

A set of functionally-defined brain regions with improved representation of the subcortex and cerebellum.

An important aspect of network-based analysis is robust node definition. This issue is critical for functional brain network analyses, as poor node choice can lead to spurious findings and misleading inferences about functional brain organization. Two sets of functional brain nodes from our group are well represented in the literature: (1) 264 volumetric regions of interest (ROIs) reported in Power et al., 2011, and (2) 333 cortical surface parcels reported in Gordon et al., 2016. However, subcortical and cerebellar structures are either incompletely captured or missing from these ROI sets. Therefore, properties of functional network organization involving the subcortex and cerebellum may be underappreciated thus far. Here, we apply a winner-take-all partitioning method to resting-state fMRI data to generate novel functionally-constrained ROIs in the thalamus, basal ganglia, amygdala, hippocampus, and cerebellum. We validate these ROIs in three datasets using several criteria, including agreement with existing literature and anatomical atlases. Further, we demonstrate that combining these ROIs with established cortical ROIs recapitulates and extends previously described functional network organization. This new set of ROIs is made publicly available for general use, including a full list of MNI coordinates and functional network labels.

Trait-like variants in human functional brain networks.

Resting-state functional magnetic resonance imaging (fMRI) has provided converging descriptions of group-level functional brain organization. Recent work has revealed that functional networks identified in individuals contain local features that differ from the group-level description. We define these features as network variants. Building on these studies, we ask whether distributions of network variants reflect stable, trait-like differences in brain organization. Across several datasets of highly-sampled individuals we show that 1) variants are highly stable within individuals, 2) variants are found in characteristic locations and associate with characteristic functional networks across large groups, 3) task-evoked signals in variants demonstrate a link to functional variation, and 4) individuals cluster into subgroups on the basis of variant characteristics that are related to differences in behavior. These results suggest that distributions of network variants may reflect stable, trait-like, functionally relevant individual differences in functional brain organization.

The State of Resting State Networks.

Functional MRI (fMRI) is currently used for pre-surgical planning, but is often limited to information on the motor and language systems. Resting state fMRI can provide more information on multiple other networks to the neurosurgeon and neuroradiologist; however, currently, these networks are not well known among clinicians. The purpose of this manuscript is to provide an introduction to these networks for the clinician and to discuss how they could be used in the future for precise and individualized surgical planning. We provide a short introduction to resting state fMRI and discuss multiple currently accepted resting state networks with a review of the literature. We review the characteristics and function of multiple somatosensory, association, and other networks. We discuss the concept of critical nodes in the brain and how the neurosurgeon can use this information to individually customize patient care. Although further research is necessary, future application of pre-surgical planning will require consideration of networks other than just motor and language in order to minimize post-surgical morbidity and customize patient care.

Re-emergence of modular brain networks in stroke recovery.

Studies of stroke have identified local reorganization in perilesional tissue. However, because the brain is highly networked, strokes also broadly alter the brain's global network organization. Here, we assess brain network structure longitudinally in adult stroke patients using resting state fMRI. The topology and boundaries of cortical regions remain grossly unchanged across recovery. In contrast, the modularity of brain systems i.e. the degree of integration within and segregation between networks, was significantly reduced sub-acutely (n = 107), but partially recovered by 3 months (n = 85), and 1 year (n = 67). Importantly, network recovery correlated with recovery from language, spatial memory, and attention deficits, but not motor or visual deficits. Finally, in-depth single subject analyses were conducted using tools for visualization of changes in brain networks over time. This exploration indicated that changes in modularity during successful recovery reflect specific alterations in the relationships between different networks. For example, in a patient with left temporo-parietal stroke and severe aphasia, sub-acute loss of modularity reflected loss of association between frontal and temporo-parietal regions bi-hemispherically across multiple modules. These long-distance connections then returned over time, paralleling aphasia recovery. This work establishes the potential importance of normalization of large-scale modular brain systems in stroke recovery.

Cognitive manipulation of brain electric microstates.

EEG studies of wakeful rest have shown that there are brief periods in which global electrical brain activity on the scalp remains semi-stable (so-called microstates). Topographical analyses of this activity have revealed that much of the variance is explained by four distinct microstates that occur in a repetitive sequence. A recent fMRI study showed that these four microstates correlated with four known functional systems, each of which is activated by specific cognitive functions and sensory inputs. The present study used high density EEG to examine the degree to which spatial and temporal properties of microstates may be altered by manipulating cognitive task (a serial subtraction task vs. wakeful rest) and the availability of visual information (eyes open vs. eyes closed conditions). The hypothesis was that parameters of microstate D would be altered during the serial subtraction task because it is correlated with regions that are part of the dorsal attention functional system. It was also expected that the sequence of microstates would preferentially transition from all other microstates to microstate D during the task as compared to rest. Finally, it was hypothesized that the eyes open condition would significantly increase one or more microstate parameters associated with microstate B, which is associated with the visual system. Topographical analyses indicated that the duration, coverage, and occurrence of microstate D were significantly higher during the cognitive task compared to wakeful rest; in addition, microstate C, which is associated with regions that are part of the default mode and cognitive control systems, was very sensitive to the task manipulation, showing significantly decreased duration, coverage, and occurrence during the task condition compared to rest. Moreover, microstate B was altered by manipulations of visual input, with increased occurrence and coverage in the eyes open condition. In addition, during the eyes open condition microstates A and D had significantly shorter durations, while C had increased occurrence. Microstate D had decreased coverage in the eyes open condition. Finally, at least 15 microstates (identified via k-means clustering) were required to explain a similar amount of variance of EEG activity as previously published values. These results support important aspects of our hypotheses and demonstrate that cognitive manipulation of microstates is possible, but the relationships between microstates and their corresponding functional systems are complex. Moreover, there may be more than four primary microstates.

Data Quality Influences Observed Links Between Functional Connectivity and Behavior.

A growing field of research explores links between behavioral measures and functional connectivity (FC) assessed using resting-state functional magnetic resonance imaging. Recent studies suggest that measurement of these relationships may be corrupted by head motion artifact. Using data from the Human Connectome Project (HCP), we find that a surprising number of behavioral, demographic, and physiological measures (23 of 122), including fluid intelligence, reading ability, weight, and psychiatric diagnostic scales, correlate with head motion. We demonstrate that "trait" (across-subject) and "state" (across-day, within-subject) effects of motion on FC are remarkably similar in HCP data, suggesting that state effects of motion could potentially mimic trait correlates of behavior. Thus, head motion is a likely source of systematic errors (bias) in the measurement of FC:behavior relationships. Next, we show that data cleaning strategies reduce the influence of head motion and substantially alter previously reported FC:behavior relationship. Our results suggest that spurious relationships mediated by head motion may be widespread in studies linking FC to behavior.