Karen Caeyenberghs

Overcoming the effects of false positives and threshold bias in graph theoretical analyses of neuroimaging data

Graph theory (GT) is a powerful framework for quantifying topological features of neuroimaging-derived functional and structural networks. However, false positive (FP) connections arise frequently and influence the inferred topology of networks. Thresholding is often used to overcome this problem, but an appropriate threshold often relies on a priori assumptions, which will alter inferred network topologies. Four common network metrics (global efficiency, mean clustering coefficient, mean betweenness and smallworldness) were tested using a model tractography dataset. It was found that all four network metrics were significantly affected even by just one FP. Results also show that thresholding effectively dampens the impact of FPs, but at the expense of adding significant bias to network metrics. In a larger number (n = 248) of tractography datasets, statistics were computed across random group permutations for a range of thresholds, revealing that statistics for network metrics varied significantly more than for non-network metrics (i.e., number of streamlines and number of edges). Varying degrees of network atrophy were introduced artificially to half the datasets, to test sensitivity to genuine group differences. For some network metrics, this atrophy was detected as significant (p < 0.05, determined using permutation testing) only across a limited range of thresholds. We propose a multi-threshold permutation correction (MTPC) method, based on the cluster-enhanced permutation correction approach, to identify sustained significant effects across clusters of thresholds. This approach minimises requirements to determine a single threshold a priori. We demonstrate improved sensitivity of MTPC-corrected metrics to genuine group effects compared to an existing approach and demonstrate the use of MTPC on a previously published network analysis of tractography data derived from a clinical population. In conclusion, we show that there are large biases and instability induced by thresholding, making statistical comparisons of network metrics difficult. However, by testing for effects across multiple thresholds using MTPC, true group differences can be robustly identified.

Cognitive and neuroimaging findings in developmental coordination disorder: new insights from a systematic review of recent research

To better understand the neural and performance factors that may underlie developmental coordination disorder (DCD), and implications for a multi‐component account.

Schizophrenia-like topological changes in the structural connectome of individuals with subclinical psychotic experiences

Schizophrenia is often regarded as a “dysconnectivity” disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population‐based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion‐weighted MRI. Whole‐brain structural connectomes were derived and a range of global and local GT‐metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair‐wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair‐wise connections illustrates that, at less severe stages of psychosis, white‐matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness. Hum Brain Mapp 36:2629–2643, 2015.© 2015 TheAuthors Human Brain Mapping Published by Wiley Periodicals, Inc.

Microstructural Integrity of the Superior Cerebellar Peduncle Is Associated with an Impaired Proprioceptive Weighting Capacity in Individuals with Non-Specific Low Back Pain

Introduction Postural control is a complex sensorimotor task that requires an intact network of white matter connections. The ability to weight proprioceptive signals is crucial for postural control. However, research into central processing of proprioceptive signals for postural control is lacking. This is specifically of interest in individuals with non-specific low back pain (NSLBP), because impairments in postural control have been observed as possible underlying mechanisms of NSLBP. Therefore, the objective was to investigate potential differences in sensorimotor white matter microstructure between individuals with NSLBP and healthy controls, and to determine whether the alterations in individuals with NSLBP are associated with the capacity to weight proprioceptive signals for postural control. Methods The contribution of proprioceptive signals from the ankle and back muscles to postural control was evaluated by local muscle vibration in 18 individuals with NSLBP and 18 healthy controls. Center of pressure displacement in response to muscle vibration was determined during upright standing on a stable and unstable support surface. Diffusion magnetic resonance imaging was applied to examine whether this proprioceptive contribution was associated with sensorimotor white matter microstructure. Results Individuals with NSLBP showed a trend towards a reduced fractional anisotropy along the left superior cerebellar peduncle compared to healthy controls (p = 0.039). The impaired microstructural integrity of the superior cerebellar peduncle in individuals with NSLBP was significantly correlated with the response to ankle muscle vibration (p<0.003). Conclusions In individuals with NSLBP, a decreased integrity of the superior cerebellar peduncle was associated with an increased reliance on ankle muscle proprioception, even on unstable support surface, which implies an impaired proprioceptive weighting capacity. Our findings emphasize the importance of the superior cerebellar peduncle in proprioceptive weighting for postural control in individuals with NSLBP.

Dynamics of the Human Structural Connectome Underlying Working Memory Training.

Brain region-specific changes have been demonstrated with a variety of cognitive training interventions. The effect of cognitive training on brain subnetworks in humans, however, remains largely unknown, with studies limited to functional networks. Here, we used a well-established working memory training program and state-of-the art neuroimaging methods in 40 healthy adults (21 females, mean age 26.5 years). Near and far-transfer training effects were assessed using computerized working memory and executive function tasks. Adaptive working memory training led to improvement on (non)trained working memory tasks and generalization to tasks of reasoning and inhibition. Graph theoretical analysis of the structural (white matter) network connectivity (“connectome”) revealed increased global integration within a frontoparietal attention network following adaptive working memory training compared with the nonadaptive group. Furthermore, the impact on the outcome of graph theoretical analyses of different white matter metrics to infer “connection strength” was evaluated. Increased efficiency of the frontoparietal network was best captured when using connection strengths derived from MR metrics that are thought to be more sensitive to differences in myelination (putatively indexed by the [quantitative] longitudinal relaxation rate, R1) than previously used diffusion MRI metrics (fractional anisotropy or fiber-tracking recovered streamlines). Our findings emphasize the critical role of specific microstructural markers in providing important hints toward the mechanisms underpinning training-induced plasticity that may drive working memory improvement in clinical populations. SIGNIFICANCE STATEMENT This is the first study to explore training-induced changes in the structural connectome using a well-controlled design to examine cognitive training with up-to-date neuroimaging methods. We found changes in global integration based on white matter connectivity within a frontoparietal attention network following adaptive working memory training compared with a nonadaptive comparison group. Furthermore, the impact of different diffusion MR metrics and more specific markers of white matter on the graph theoretical findings was evaluated. An increase in network global efficiency following working memory training was best captured when connection strengths were weighted by MR relaxation rates (influenced by myelination). These results are important for the optimization of cognitive training programs for healthy individuals and people with brain disease.

Coupling online control and inhibitory systems in children with Developmental Coordination Disorder: Goal-directed reaching

For children with Developmental Coordination Disorder (DCD), the real-time coupling between frontal executive function and online motor control has not been explored despite reported deficits in each domain. The aim of the present study was to investigate how children with DCD enlist online control under task constraints that compel the need for inhibitory control. A total of 129 school children were sampled from mainstream primary schools. Forty-two children who met research criteria for DCD were compared with 87 typically developing controls on a modified double-jump reaching task. Children within each skill group were divided into three age bands: younger (6-7 years), mid-aged (8-9), and older (10-12). Online control was compared between groups as a function of trial type (non-jump, jump, anti-jump). Overall, results showed that while movement times were similar between skill groups under simple task constraints (non-jump), on perturbation (or jump) trials the DCD group were significantly slower than controls and corrected trajectories later. Critically, the DCD group was further disadvantaged by anti-jump trials where inhibitory control was required; however, this effect reduced with age. While coupling online control and executive systems is not well developed in younger and mid-aged children, there is evidence of age-appropriate coupling in older children. Longitudinal data are needed to clarify this intriguing finding. The theoretical and applied implications of these results are discussed.

Motor imagery training enhances motor skill in children with DCD: A replication study

BACKGROUND Children with impaired motor coordination (or DCD) have difficulty using motor imagery. We have suggested that this difficulty is explained by the internal modeling deficit (IMD) hypothesis of DCD. Our previous training study lent support for this hypothesis by showing that a computerized imagery training protocol (involving action observation, and mental- and overt-rehearsal) was equally effective to perceptual-motor therapy (PMT) in promoting motor skill acquisition. AIMS The study presented here was designed to replicate and extend this finding, targeting a select group of children with moderate-to-severe DCD. METHODS AND PROCEDURES All 36 children with DCD who participated were referred to the study and scored below the 10th percentile for their age on the Movement Assessment Battery for Children (MABC). Using a randomized control trial, the referred children were assigned randomly to one of three groups using a blocked procedure: imagery training, perceptual-motor training (PMT), and wait-list control. Motor proficiency was measured using the MABC, pre and post-training. Individual training consisted of 60-min sessions, conducted once a week for 5 weeks. RESULTS Results showed that the imagery protocol was equally effective as PMT in promoting motor skill acquisition, with moderate-to-large effect sizes. Individual differences showed that the majority of children in the two intervention groups improved their motor performance significantly. CONCLUSIONS Overall, these results further support the use of motor imagery protocols in the treatment of DCD, and tentative support for the IMD hypothesis. Developmental and dose issues in the implementation of imagery-based intervention are discussed.

Task complexity and location specific changes of cortical thickness in executive and salience networks after working memory training

Novel activities and experiences shape the brains structure and organisation and, hence, our behaviour. However, evidence from structural plasticity studies remains mixed and the neural correlates of learning and practice are still poorly understood. We conducted a robustly designed study into grey matter plasticity following 2 months of working memory training. We generated a priori hypotheses regarding the location of plastic effects across three cognitive control networks (executive, anterior salience and basal ganglia networks), and compared the effects of adaptive training (n = 20) with a well-matched active control group (n = 20) which differed in training complexity and included extensive cognitive assessment before and after the training. Adaptive training relative to control activities resulted in a complex pattern of subtle and localised structural changes: Training was associated with increases in cortical thickness in right-lateralised executive regions, notably the right caudal middle frontal cortex, as well as increases in the volume of the left pallidum. In addition the training group showed reductions of thickness in the right insula, which were correlated with training-induced improvements in backward digit span performance. Unexpectedly, control activities were associated with reductions in thickness in the right pars triangularis. These results suggest that the direction of activity-induced plastic changes depend on the level of training complexity as well as brain location. These observations are consistent with the view that the brain responds dynamically to environmental demands by focusing resources on task relevant networks and eliminating irrelevant processing for the purpose of energy reduction.

Coupling of online control and inhibitory systems in children with atypical motor development: A growth curve modelling study

INTRODUCTION Previous research indicates that children with Developmental Coordination Disorder (DCD) show deficits performing online corrections, an issue exacerbated by adding inhibitory constraints; however, cross-sectional data suggests that these deficits may reduce with age. Using a longitudinal design, the aim of the study presented here was to model the coupling that occurs between inhibitory systems and (predictive) online control in typically developing children (TDC) and in those with Developmental Coordination Disorder (DCD) over an extended period of time, using a framework of interactive specialization. We predicted that TDC would show a non-linear growth pattern, consistent with re-organisation in the coupling during the middle childhood period, while DCD would display a developmental lag. METHOD A group of 196 children (111 girls and 85 boys) aged between 6 and 12years participated in the study. Children were classified as DCD according to research criteria. Using a cohort sequential design, both TDC and DCD groups were divided into age cohorts. Predictive (online) control was defined operationally by performance on a Double-Jump Reaching Task (DJRT), which was assessed at 6-month intervals over two years (5 time points in total). Inhibitory control was examined using an anti-jump condition of the DJRT paradigm whereby children were instructed to touch a target location in the hemispace opposite a cued location. RESULTS For the TDC group, model comparison using growth curve analysis revealed that a quadratic trend was the most appropriate fit with evidence of rapid improvement in anti-reach performance up until middle childhood (around 8-9years of age), followed by a more gradual rate of improvement into late childhood and early adolescence. This pattern was evident on both chronometric and kinematic measures. In contrast, for children with DCD, a linear function provided the best to fit on the key metrics, with a slower rate of improvement than controls. CONCLUSION We conclude that children with DCD require a more extended period of development to effectively couple online motor control and executive systems when completing anti-reach movements, whereas TDC show rapid improvement in early and middle childhood. These group differences in growth curves are likely to reflect a maturational lag in the development of motor-cognitive networks in children with DCD.

Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis.

Objective Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. Methods Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. Results Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. Conclusions Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.