Altered Inferior Parietal Functional Connectivity is Correlated with Praxis and Social Skill Performance in Children with Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) have difficulties perceiving and producing skilled gestures, or praxis. The inferior parietal lobule (IPL) is crucial to praxis acquisition and expression, yet how IPL connectivity contributes to autism-associated impairments in praxis as well as social-communicative skill remains unclear. Using resting-state functional magnetic resonance imaging, we applied independent component analysis to test how IPL connectivity relates to praxis and social-communicative skills in children with and without ASD. Across all children (with/without ASD), praxis positively correlated with connectivity of left posterior-IPL with the left dorsal premotor cortex and with the bilateral posterior/medial parietal cortex. Praxis also correlated with connectivity of right central-IPL connectivity with the left intraparietal sulcus and medial parietal lobe. Further, in children with ASD, poorer praxis and social-communicative skills both correlated with weaker right central-IPL connectivity with the left cerebellum, posterior cingulate, and right dorsal premotor cortex. Our findings suggest that IPL connectivity is linked to praxis development, that contributions arise bilaterally, and that right IPL connectivity is associated with impaired praxis and social-communicative skills in autism. The findings underscore the potential impact of IPL connectivity and impaired skill acquisition on the development of a range of social-communicative and motor functions during childhood, including autism-associated impairments.

Beyond modularity: Fine-scale mechanisms and rules for brain network reconfiguration.

The human brain is in constant flux, as distinct areas engage in transient communication to support basic behaviors as well as complex cognition. The collection of interactions between cortical and subcortical areas forms a functional brain network whose topology evolves with time. Despite the nontrivial dynamics that are germane to this networked system, experimental evidence demonstrates that functional interactions organize into putative brain systems that facilitate different facets of cognitive computation. We hypothesize that such dynamic functional networks are organized around a set of rules that constrain their spatial architecture - which brain regions may functionally interact - and their temporal architecture - how these interactions fluctuate over time. To objectively uncover these organizing principles, we apply an unsupervised machine learning approach called non-negative matrix factorization to time-evolving, resting state functional networks in 20 healthy subjects. This machine learning approach automatically groups temporally co-varying functional interactions into subgraphs that represent putative topological modes of dynamic functional architecture. We find that subgraphs are stratified based on both the underlying modular organization and the topographical distance of their strongest interactions: while many subgraphs are largely contained within modules, others span between modules and are expressed differently over time. The relationship between dynamic subgraphs and modular architecture is further highlighted by the ability of time-varying subgraph expression to explain inter-individual differences in module reorganization. Collectively, these results point to the critical role that subgraphs play in constraining the topography and topology of functional brain networks. More broadly, this machine learning approach opens a new door for understanding the architecture of dynamic functional networks during both task and rest states, and for probing alterations of that architecture in disease.

Predicting future learning from baseline network architecture.

Human behavior and cognition result from a complex pattern of interactions between brain regions. The flexible reconfiguration of these patterns enables behavioral adaptation, such as the acquisition of a new motor skill. Yet, the degree to which these reconfigurations depend on the brain's baseline sensorimotor integration is far from understood. Here, we asked whether spontaneous fluctuations in sensorimotor networks at baseline were predictive of individual differences in future learning. We analyzed functional MRI data from 19 participants prior to six weeks of training on a new motor skill. We found that visual-motor connectivity was inversely related to learning rate: sensorimotor autonomy at baseline corresponded to faster learning in the future. Using three additional scans, we found that visual-motor connectivity at baseline is a relatively stable individual trait. These results suggest that individual differences in motor skill learning can be predicted from sensorimotor autonomy at baseline prior to task execution.

Brain state flexibility accompanies motor-skill acquisition.

Learning requires the traversal of inherently distinct cognitive states to produce behavioral adaptation. Yet, tools to explicitly measure these states with non-invasive imaging - and to assess their dynamics during learning - remain limited. Here, we describe an approach based on a distinct application of graph theory in which points in time are represented by network nodes, and similarities in brain states between two different time points are represented as network edges. We use a graph-based clustering technique to identify clusters of time points representing canonical brain states, and to assess the manner in which the brain moves from one state to another as learning progresses. We observe the presence of two primary states characterized by either high activation in sensorimotor cortex or high activation in a frontal-subcortical system. Flexible switching among these primary states and other less common states becomes more frequent as learning progresses, and is inversely correlated with individual differences in learning rate. These results are consistent with the notion that the development of automaticity is associated with a greater freedom to use cognitive resources for other processes. Taken together, our work offers new insights into the constrained, low dimensional nature of brain dynamics characteristic of early learning, which give way to less constrained, high-dimensional dynamics in later learning.

Structural Pathways Supporting Swift Acquisition of New Visuomotor Skills.

Human skill learning requires fine-scale coordination of distributed networks of brain regions linked by white matter tracts to allow for effective information transmission. Yet how individual differences in these anatomical pathways may impact individual differences in learning remains far from understood. Here, we test the hypothesis that individual differences in structural organization of networks supporting task performance predict individual differences in the rate at which humans learn a visuomotor skill. Over the course of 6 weeks, 20 healthy adult subjects practiced a discrete sequence production task, learning a sequence of finger movements based on discrete visual cues. We collected structural imaging data, and using deterministic tractography generated structural networks for each participant to identify streamlines connecting cortical and subcortical brain regions. We observed that increased white matter connectivity linking early visual regions was associated with a faster learning rate. Moreover, the strength of multiedge paths between motor and visual modules was also correlated with learning rate, supporting the potential role of extended sets of polysynaptic connections in successful skill acquisition. Our results demonstrate that estimates of anatomical connectivity from white matter microstructure can be used to predict future individual differences in the capacity to learn a new motor-visual skill, and that these predictions are supported both by direct connectivity in visual cortex and indirect connectivity between visual cortex and motor cortex.

Cohesive network reconfiguration accompanies extended training.

Human behavior is supported by flexible neurophysiological processes that enable the fine-scale manipulation of information across distributed neural circuits. Yet, approaches for understanding the dynamics of these circuit interactions have been limited. One promising avenue for quantifying and describing these dynamics lies in multilayer network models. Here, networks are composed of nodes (which represent brain regions) and time-dependent edges (which represent statistical similarities in activity time series). We use this approach to examine functional connectivity measured by non-invasive neuroimaging techniques. These multilayer network models facilitate the examination of changes in the pattern of statistical interactions between large-scale brain regions that might facilitate behavior. In this study, we define and exercise two novel measures of network reconfiguration, and demonstrate their utility in neuroimaging data acquired as healthy adult human subjects learn a new motor skill. In particular, we identify putative functional modules in multilayer networks and characterize the degree to which nodes switch between modules. Next, we define cohesive switches, in which a set of nodes moves between modules together as a group, and we define disjoint switches, in which a single node moves between modules independently from other nodes. Together, these two concepts offer complementary yet distinct insights into the changes in functional connectivity that accompany motor learning. More generally, our work offers statistical tools that other researchers can use to better understand the reconfiguration patterns of functional connectivity over time. Hum Brain Mapp 38:4744-4759, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The Human Motor System Supports Sequence-Specific Representations over Multiple Training-Dependent Timescales.

Motor sequence learning is associated with increasing and decreasing motor system activity. Here, we ask whether sequence-specific activity is contingent upon the time interval and absolute amount of training over which the skill is acquired. We hypothesize that within each motor region, the strength of any sequence representation is a non-linear function that can be characterized by 3 timescales. We had subjects train for 6 weeks and measured brain activity with functional magnetic resonance imaging. We used repetition suppression (RS) to isolate sequence-specific representations while controlling for effects related to kinematics and general task familiarity. Following a baseline training session, primary and secondary motor regions demonstrated rapidly increasing RS. With continued training, there was evidence for skill-specific efficiency, characterized by a dramatic decrease in motor system RS. In contrast, after performance had reached a plateau, further training led to a pattern of slowly increasing RS in the contralateral sensorimotor cortex, supplementary motor area, ventral premotor cortex, and anterior cerebellum consistent with skill-specific specialization. Importantly, many motor areas show changes involving more than 1 of these 3 timescales, underscoring the capacity of the motor system to flexibly represent a sequence based on the amount of prior experience.

Multifaceted aspects of chunking enable robust algorithms.

Sequence production tasks are a standard tool to analyze motor learning, consolidation, and habituation. As sequences are learned, movements are typically grouped into subsets or chunks. For example, most Americans memorize telephone numbers in two chunks of three digits, and one chunk of four. Studies generally use response times or error rates to estimate how subjects chunk, and these estimates are often related to physiological data. Here we show that chunking is simultaneously reflected in reaction times, errors, and their correlations. This multimodal structure enables us to propose a Bayesian algorithm that better estimates chunks while avoiding overfitting. Our algorithm reveals previously unknown behavioral structure, such as an increased error correlations with training, and promises a useful tool for the characterization of many forms of sequential motor behavior.

Task-based core-periphery organization of human brain dynamics.

As a person learns a new skill, distinct synapses, brain regions, and circuits are engaged and change over time. In this paper, we develop methods to examine patterns of correlated activity across a large set of brain regions. Our goal is to identify properties that enable robust learning of a motor skill. We measure brain activity during motor sequencing and characterize network properties based on coherent activity between brain regions. Using recently developed algorithms to detect time-evolving communities, we find that the complex reconfiguration patterns of the brain's putative functional modules that control learning can be described parsimoniously by the combined presence of a relatively stiff temporal core that is composed primarily of sensorimotor and visual regions whose connectivity changes little in time and a flexible temporal periphery that is composed primarily of multimodal association regions whose connectivity changes frequently. The separation between temporal core and periphery changes over the course of training and, importantly, is a good predictor of individual differences in learning success. The core of dynamically stiff regions exhibits dense connectivity, which is consistent with notions of core-periphery organization established previously in social networks. Our results demonstrate that core-periphery organization provides an insightful way to understand how putative functional modules are linked. This, in turn, enables the prediction of fundamental human capacities, including the production of complex goal-directed behavior.

Dynamic reconfiguration of human brain networks during learning.

Human learning is a complex phenomenon requiring flexibility to adapt existing brain function and precision in selecting new neurophysiological activities to drive desired behavior. These two attributes--flexibility and selection--must operate over multiple temporal scales as performance of a skill changes from being slow and challenging to being fast and automatic. Such selective adaptability is naturally provided by modular structure, which plays a critical role in evolution, development, and optimal network function. Using functional connectivity measurements of brain activity acquired from initial training through mastery of a simple motor skill, we investigate the role of modularity in human learning by identifying dynamic changes of modular organization spanning multiple temporal scales. Our results indicate that flexibility, which we measure by the allegiance of nodes to modules, in one experimental session predicts the relative amount of learning in a future session. We also develop a general statistical framework for the identification of modular architectures in evolving systems, which is broadly applicable to disciplines where network adaptability is crucial to the understanding of system performance.

Cross-linked structure of network evolution.

We study the temporal co-variation of network co-evolution via the cross-link structure of networks, for which we take advantage of the formalism of hypergraphs to map cross-link structures back to network nodes. We investigate two sets of temporal network data in detail. In a network of coupled nonlinear oscillators, hyperedges that consist of network edges with temporally co-varying weights uncover the driving co-evolution patterns of edge weight dynamics both within and between oscillator communities. In the human brain, networks that represent temporal changes in brain activity during learning exhibit early co-evolution that then settles down with practice. Subsequent decreases in hyperedge size are consistent with emergence of an autonomous subgraph whose dynamics no longer depends on other parts of the network. Our results on real and synthetic networks give a poignant demonstration of the ability of cross-link structure to uncover unexpected co-evolution attributes in both real and synthetic dynamical systems. This, in turn, illustrates the utility of analyzing cross-links for investigating the structure of temporal networks.

Contributions from the left PMd and the SMA during sequence retrieval as determined by depth of training.

The dorsal premotor cortex (PMd) and the supplementary motor area (SMA) are critical for the acquisition and expression of sequential behavior, but little is known regarding how these regions are recruited when we must simultaneously acquire multiple sequences under different amounts of training. We hypothesized that these regions contribute to the retrieval of sequences at different familiarity levels, with the left PMd supporting sequences of moderate familiarity and the SMA supporting sequences of greater familiarity. Double-pulse transcranial magnetic stimulation (TMS) was applied during the retrieval of six sequences previously learned under three different amounts of exposure during 30 days of training using a discrete sequence production task. TMS led to a significant interaction of sequence error between depth of training and stimulation location. Stimulation of the left PMd increased error during moderate sequence retrieval, whereas stimulation of the SMA increased error during the retrieval of both moderately and extensively trained sequences. The lack of a double dissociation fails to support a direct correspondence between brain region and putative behavioral learning stage. Instead, the interaction suggests that SMA and PMd support the expression of sequences over different, albeit overlapping, time scales. Separate analysis of sequence initiation time did not demonstrate any significant difference between moderately and extensively trained sequences. Instead, stimulation to either region quickened sequence initiation for these sequences, but not for those sequences with poor retrieval performance. This supports the general role of these premotor regions in the maintenance of specific sequence knowledge prior to movement onset.

Robust detection of dynamic community structure in networks.

We describe techniques for the robust detection of community structure in some classes of time-dependent networks. Specifically, we consider the use of statistical null models for facilitating the principled identification of structural modules in semi-decomposable systems. Null models play an important role both in the optimization of quality functions such as modularity and in the subsequent assessment of the statistical validity of identified community structure. We examine the sensitivity of such methods to model parameters and show how comparisons to null models can help identify system scales. By considering a large number of optimizations, we quantify the variance of network diagnostics over optimizations ("optimization variance") and over randomizations of network structure ("randomization variance"). Because the modularity quality function typically has a large number of nearly degenerate local optima for networks constructed using real data, we develop a method to construct representative partitions that uses a null model to correct for statistical noise in sets of partitions. To illustrate our results, we employ ensembles of time-dependent networks extracted from both nonlinear oscillators and empirical neuroscience data.

Social supports moderate the effects of child adversity on neural correlates of threat processing.

BACKGROUND: Child abuse and other forms of adversity are associated with alterations in threat processing and emotion regulation brain circuits. OBJECTIVE: The goal of the current investigation is to determine if the availability of positive social support can ameliorate the negative impact of adversity on these brain systems. PARTICIPANTS AND SETTING: Subjects included 55 children ages 7-16 (X = 11.8, SD = 2.0). Approximately one-third of the cohort had no significant history of adversity, one-third had a history of moderate adversity, and one-third had a history of severe adversity. Brain imaging was conducted at the University of Vermont using a 3.0 T Philips scanner. METHODS: The Emotional Go-NoGo task with fearful and calm facial stimuli was used to assess the neural correlates of threat processing and emotion regulation in children during functional magnetic resonance imaging (fMRI). Dimensional measures of anxiety, social supports, and children's adverse experiences were also obtained. RESULTS: A conjunction analysis was used to test if trauma-related brain activation in responding to fearful vs. calm targets was impacted by social support. This approach identified multiple activation foci, including a cluster extending from the left amygdala to several other key brain regions involved in emotion regulation, including the orbitofrontal cortex, anterior cingulate cortex (ACC), anterior insula, nucleus accumbens, and frontal pole (Family Wise Error (FWE) correction, p < 0.05). CONCLUSIONS: Greater social support may reduce the effect that adversity has on neural processing of threat stimuli, consistent with the protective role of positive supports in promoting resilience and recovery demonstrated in the literature.

Tubulin Polymerization Promoting Protein (TPPP) gene methylation and corpus callosum measures in maltreated children.

The goal of the current study was to evaluate the impact of Tubulin Polymerization Promoting Protein (TPPP) methylation on structural and fractional anisotropy (FA) corpus callosum (CC) measures. TPPP is involved in the development of white matter tracts in the brain and was implicated in stress-related psychiatric disorders in an unbiased whole epigenome methylation study. The cohort included 63 participants (11.73 y/o ±1.91) from a larger study investigating risk and resilience in maltreated children. Voxel-based morphometry (VBM) was used to process the structural data, fractional anisotropy (FA) was determined using an atlas-based approach, and DNA specimens were derived from saliva in two batches using the 450 K (N = 39) and 850 K (N = 24) Illumina arrays, with the data from each batch analyzed separately. After controlling for multiple comparisons and relevant covariates (e.g., demographics, brain volume, cell composition, 3 PCs), 850 K derived TPPP methylation values, in interaction with a dimensional measure of children's trauma experiences, predicted left and right CC body volumes and genu, body and splenium FA (p < .007, all comparisons). The findings in the splenium replicated in subjects with the 450 K data. The results extend prior investigations and suggest a role for TPPP in brain changes associated with stress-related psychiatric disorders.

Neural substrates of practice structure that support future off-line learning.

Off-line learning is facilitated when motor skills are acquired under a random practice schedule and retention suffers when a similar set of motor skills are practiced under a blocked schedule. The current study identified the neural correlates of a random training schedule while participants learned a set of four-element finger sequences using their nondominant hand during functional magnetic resonance imaging. A go/no go task was used to separately probe brain areas supporting sequence preparation and production. By the end of training, the random practice schedule, relative to the block schedule, recruited a broad premotor-parietal network as well as sensorimotor and subcortical regions during both preparation and production trials, despite equivalent motor performance. Longitudinal analysis demonstrated that preparation-related activity under a random schedule remained stable or increased over time. The blocked schedule showed the opposite pattern. Across individual subjects, successful skill retention was correlated with greater activity at the end of training in the ipsilateral left motor cortex, for both preparation and production. This is consistent with recent evidence that attributes off-line learning to training-related processing within primary motor cortex. These results reflect the importance of an overlooked aspect of motor skill learning. Specifically, how trials are organized during training-with a random schedule-provides an effective basis for the formation of enduring motor memories, through enhanced engagement of core regions involved in the active preparation and implementation of motor programs.

Transient disruption of M1 during response planning impairs subsequent offline consolidation.

Transcranial magnetic stimulation (TMS) was used to probe the involvement of the left primary motor cortex (M1) in the consolidation of a sequencing skill. In particular we asked: (1) if M1 is involved in consolidation of planning processes prior to response execution (2) whether movement preparation and movement execution can undergo consolidation independently and (3) whether sequence consolidation can occur in a stimulus specific manner. TMS was applied to left M1 while subjects prepared left hand sequential finger responses for three different movement sequences, presented in an interleaved fashion. Subjects also trained on three control sequences, where no TMS was applied. Disruption of subsequent consolidation was observed, but only for sequences where subjects had been exposed to TMS during training. Further, reduced consolidation was only observed for movement preparation, not movement execution. We conclude that left M1 is causally involved in the consolidation of effective response planning for left hand movements prior to response execution, and mediates consolidation in a sequence specific manner. These results provide important new insights into the role of M1 in sequential memory consolidation and sequence response planning.

Methylation in OTX2 and related genes, maltreatment, and depression in children.

Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

Randomized, Placebo-controlled Crossover Study of Dalfampridine Extended-release in Transverse Myelitis.

BACKGROUND: Dalfampridine has the potential to be effective in patients with transverse myelitis (TM) as this rare disorder shares some clinical and pathogenic similarities with multiple sclerosis. METHODS: This is a randomized, double-blind, placebo-controlled crossover study of dalfampridine extended-release (D-ER, Ampyra®). Sixteen adult study participants with monophasic TM confirmed by MRI were enrolled if their baseline timed 25-foot walking speed was between 5 and 60 seconds. Participants were randomized to receive 10 mg twice-daily doses of either D-ER or placebo control for eight weeks, then crossed over to the second arm of placebo or dalfampridine for eight weeks. The primary outcome measure was the timed 25-foot walk. RESULTS: Of 16 enrolled participants, three withdrew and 13 completed the trial. Among the 13 completers, nine individuals showed an average timed walk that was faster in the D-ER arm compared to the placebo arm, but only four participants met the stricter statistical threshold to be classified as a responder. Analyses of secondary clinical outcome measures including strength, balance assessments, spasticity, and Expanded Disability Status Scale (EDSS) score showed trends toward improvement with D-ER. CONCLUSIONS: D-ER may be beneficial in TM to improve walking speed and other neurological functions.

Learning about learning: Mining human brain sub-network biomarkers from fMRI data.

Modeling the brain as a functional network can reveal the relationship between distributed neurophysiological processes and functional interactions between brain structures. Existing literature on functional brain networks focuses mainly on a battery of network properties in "resting state" employing, for example, modularity, clustering, or path length among regions. In contrast, we seek to uncover functionally connected subnetworks that predict or correlate with cohort differences and are conserved within the subjects within a cohort. We focus on differences in both the rate of learning as well as overall performance in a sensorimotor task across subjects and develop a principled approach for the discovery of discriminative subgraphs of functional connectivity based on imaging acquired during practice. We discover two statistically significant subgraph regions: one involving multiple regions in the visual cortex and another involving the parietal operculum and planum temporale. High functional coherence in the former characterizes sessions in which subjects take longer to perform the task, while high coherence in the latter is associated with high learning rate (performance improvement across trials). Our proposed methodology is general, in that it can be applied to other cognitive tasks, to study learning or to differentiate between healthy patients and patients with neurological disorders, by revealing the salient interactions among brain regions associated with the observed global state. The discovery of such significant discriminative subgraphs promises a better data-driven understanding of the dynamic brain processes associated with high-level cognitive functions.