M.P. van den Heuvel

Small-world and scale-free organization of voxel-based resting-state functional connectivity in the human brain.

The brain is a complex dynamic system of functionally connected regions. Graph theory has been successfully used to describe the organization of such dynamic systems. Recent resting-state fMRI studies have suggested that inter-regional functional connectivity shows a small-world topology, indicating an organization of the brain in highly clustered sub-networks, combined with a high level of global connectivity. In addition, a few studies have investigated a possible scale-free topology of the human brain, but the results of these studies have been inconclusive. These studies have mainly focused on inter-regional connectivity, representing the brain as a network of brain regions, requiring an arbitrary definition of such regions. However, using a voxel-wise approach allows for the model-free examination of both inter-regional as well as intra-regional connectivity and might reveal new information on network organization. Especially, a voxel-based study could give information about a possible scale-free organization of functional connectivity in the human brain. Resting-state 3 Tesla fMRI recordings of 28 healthy subjects were acquired and individual connectivity graphs were formed out of all cortical and sub-cortical voxels with connections reflecting inter-voxel functional connectivity. Graph characteristics from these connectivity networks were computed. The clustering-coefficient of these networks turned out to be much higher than the clustering-coefficient of comparable random graphs, together with a short average path length, indicating a small-world organization. Furthermore, the connectivity distribution of the number of inter-voxel connections followed a power-law scaling with an exponent close to 2, suggesting a scale-free network topology. Our findings suggest a combined small-world and scale-free organization of the functionally connected human brain. The results are interpreted as evidence for a highly efficient organization of the functionally connected brain, in which voxels are mostly connected with their direct neighbors forming clustered sub-networks, which are held together by a small number of highly connected hub-voxels that ensure a high level of overall connectivity.

Region and state specific glutamate downregulation in major depressive disorder: A meta-analysis of 1H-MRS findings

For major depressive disorder (MDD), magnetic resonance spectroscopy ((1)H-MRS) studies of glutamate, glutamine and Glx (the composite measure of mainly glutamate and glutamine) have yielded inconclusive or seemingly inconsistent results. We therefore systematically reviewed whether in vivo concentrations of glutamate, glutamine and Glx measured with (1)H-MRS differ between MDD patients and controls. Meta-analysis including meta-regression, sensitivity, statistical heterogeneity, and publication bias analyses were conducted. Glutamate and Glx concentrations were found to be lower in the anterior cingulate cortex (ACC) in patients compared to controls (standardized mean difference (SMD) for glutamate with 95% CIs: -0.86, -1.55 to -0.17; and for Glx: -1.15, -1.86 to -0.44). In addition, Glx was decreased in all brain regions together in current episode patients (SMD: -0.62, -1.17 to -0.07). We conclude that in MDD, glutamate and possibly glutamine are downregulated primarily in the ACC and during depressive states. These results fit the central role of the ACC in depressive symptomatology and suggest that in MDD changes in glutamatergic neurotransmission are state-dependent.

Effects of Aging on BOLD fMRI during Prosaccades and Antisaccades

Age affects the ability to inhibit saccadic eye movements. According to current theories, this may be associated with age-induced neurophysiological changes in the brain and with compensatory activation in frontal brain areas. In the present study, the effects of aging are assessed on brain systems that subserve generation and inhibition of saccadic eye movements. For this purpose, an event-related functional magnetic resonance imaging design was used in adults covering three age ranges (1830, 3055, and 5572 years). Group differences were controlled for task performance. Activity associated with saccadic inhibition was represented by the contrast between prosaccade and antisaccade activation. The tasks activated well-documented networks of regions known to be involved in generation and inhibition of saccadic eye movements. There was an age-related shift in activity from posterior to frontal brain regions after young adulthood. In addition, old adults demonstrated an overall reduction in the blood oxygenation level dependent (BOLD) signal in the visual and oculomotor system. Age, however, did not affect saccade inhibition activity. Mid and old adults appear to increase frontal activation to maintain performance even during simple prosaccades. The global reduction of the BOLD response in old adults could reflect a reduction in neural activity, as well as changes in the neuronal-vascular coupling. Future research should address the impact of altered vascular dynamics on neural activation and the BOLD signal.

Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder

BACKGROUND Smaller hippocampal volume has often been observed in patients with post-traumatic stress disorder (PTSD). However, there is no consensus whether this is a result of stress/trauma exposure, or constitutes a vulnerability factor for the development of PTSD. Second, it is unclear whether hippocampal volume normalizes with successful treatment of PTSD, or whether a smaller hippocampus is a risk factor for the persistence of PTSD. METHOD Magnetic resonance imaging (MRI) scans and clinical interviews were collected from 47 war veterans with PTSD, 25 healthy war veterans (combat controls) and 25 healthy non-military controls. All veterans were scanned a second time with a 6- to 8-month interval, during which PTSD patients received trauma-focused therapy. Based on post-treatment PTSD symptoms, patients were divided into a PTSD group who was in remission (n = 22) and a group in whom PTSD symptoms persisted (n = 22). MRI data were analysed with Freesurfer. RESULTS Smaller left hippocampal volume was observed in PTSD patients compared with both control groups. Hippocampal volume of the combat controls did not differ from healthy controls. Second, pre- and post-treatment analyses of the PTSD patients and combat controls revealed reduced (left) hippocampal volume only in the persistent patients at both time points. Importantly, hippocampal volume did not change with treatment. CONCLUSIONS Our findings suggest that a smaller (left) hippocampus is not the result of stress/trauma exposure. Furthermore, hippocampal volume does not increase with successful treatment. Instead, we demonstrate for the first time that a smaller (left) hippocampus constitutes a risk factor for the persistence of PTSD.

On development of functional brain connectivity in the young brain

Our brain is a complex network of structurally and functionally interconnected regions, shaped to efficiently process and integrate information. The development from a brain equipped with basic functionalities to an efficient network facilitating complex behavior starts during gestation and continues into adulthood. Resting-state functional MRI (rs-fMRI) enables the examination of developmental aspects of functional connectivity (FC) and functional brain networks. This review will discuss changes observed in the developing brain on the level of network FC from a gestational age of 20 weeks onwards. We discuss findings of resting-state fMRI studies showing that functional network development starts during gestation, creating a foundation for each of the resting-state networks (RSNs) to be established. Visual and sensorimotor areas are reported to develop first, with other networks, at different rates, increasing both in network connectivity and size over time. Reaching childhood, marked fine-tuning and specialization takes place in the regions necessary for higher-order cognitive functions.

Leader-member exchange, work engagement and job performance

Purpose – The purpose of this paper is to examine the process through which leader-member exchange (LMX) is related to followers’ job performance. Integrating the literature on LMX theory and resource theories, the authors hypothesized that the positive relationship between LMX and employee job performance is sequentially mediated by job resources (autonomy, developmental opportunities, and social support) and employee work engagement. Design/methodology/approach – In total, 847 Dutch police officers filled out an online questionnaire. Multilevel structural equation modeling was used to test the hypothesized relationships and to account for the nesting of employees in teams. Findings – Employees in high-quality LMX relationships work in a more resourceful work environment (i.e. report more developmental opportunities and social support, but not more autonomy). This resourceful work environment, in turn, facilitates work engagement and job performance. Research limitations/implications – Because of the res...

Functional network topology associated with posttraumatic stress disorder in veterans.

Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functional connectivity alterations. However, whether specific brain regions are altered in PTSD or whether the whole brain network organization differs remains unclear. PTSD can be treated with trauma-focused therapy, although only half of the patients recover after treatment. In order to better understand PTSD psychopathology our aim was to study resting state networks in PTSD before and after treatment. Resting state functional magnetic resonance images were obtained from veterans with PTSD (n = 50) and controls (combat and civilian controls; n = 54) to explore which network topology properties (degree and clustering coefficient) of which brain regions are associated with PTSD. Then, PTSD-associated brain regions were investigated before and after treatment. PTSD patients were subdivided in persistent (n = 22) and remitted PTSD patients (n = 17), and compared with combat controls (n = 22), who were also reassessed. Prior to treatment associations with PTSD were found for the degree of orbitofrontal, and temporoparietal brain regions, and for the clustering coefficient of the anterior cingulate cortex. No significant effects were found over the course of treatment. Our results are in line with previous resting state studies, showing resting state connectivity alterations in the salience network and default mode network in PTSD, and also highlight the importance of other brain regions. However, network metrics do not seem to change over the course of treatment. This study contributes to a better understanding of the psychopathology of PTSD.

Affected connectivity organization of the reward system structure in obesity

With the prevalence of obesity rapidly increasing worldwide, understanding the processes leading to excessive eating behavior becomes increasingly important. Considering the widely recognized crucial role of reward processes in food intake, we examined the white matter wiring and integrity of the anatomical reward network in obesity. Anatomical wiring of the reward network was reconstructed derived from diffusion weighted imaging in 31 obese participants and 32 normal-weight participants. Network wiring was compared in terms of the white matter volume as well as in terms of white matter microstructure, revealing lower number of streamlines and lower fiber integrity within the reward network in obese subjects. Specifically, the orbitofrontal cortex and striatum nuclei including accumbens, caudate and putamen showed lower strength and network clustering in the obesity group as compared to healthy controls. Our results provide evidence for obesity-related disruptions of global and local anatomical connectivity of the reward circuitry in regions that are key in the reinforcing mechanisms of eating-behavior processes.

Connectomics-based structural network alterations in obsessive-compulsive disorder

Given the strong involvement of affect in obsessive-compulsive disorder (OCD) and recent findings, the current cortico-striato-thalamo-cortical (CSTC) model of pathophysiology has repeatedly been questioned regarding the specific role of regions involved in emotion processing such as limbic areas. Employing a connectomics approach enables us to characterize structural connectivity on a whole-brain level, extending beyond the CSTC circuitry. Whole-brain structural networks of 41 patients and 42 matched healthy controls were analyzed based on 83 × 83 connectivity matrices derived from cortical and subcortical parcellation of structural T1-weighted magnetic resonance scans and deterministic fiber tracking based on diffusion tensor imaging data. To assess group differences in structural connectivity, the framework of network-based statistic (NBS) was applied. Graph theoretical measures were calculated to further assess local and global network characteristics. The NBS analysis revealed a single network consistently displaying decreased structural connectivity in patients comprising orbitofrontal, striatal, insula and temporo-limbic areas. In addition, graph theoretical measures indicated local alterations for amygdala and temporal pole while the overall topology of the network was preserved. To the best of our knowledge, this is the first study combining the NBS with graph theoretical measures in OCD. Along with regions commonly described in the CSTC model of pathophysiology, our results indicate an involvement of mainly temporo-limbic regions typically associated with emotion processing supporting their importance for neurobiological alterations in OCD.

Functional architecture of the human brain

This special issue on the Functional Architecture of the Brain brings together some of the latest directions in research into the organization of functional brain networks and connectivity. The issue comprises 13 high-quality review articles from leaders in the field, providing state-of-the-art coverage of selected topics including multiscale brain networks, functional connectivity dynamics, computational network modeling, network effects of TMS, and functional brain organization across development and during sleep. One theme that cuts across most of the papers in this issue is the rich multiscale structure of brain network dynamics, from the gradual maturational and degenerative changes evident across the lifespan, to the rapid and transitory network reconfigurations seen in response to new contextual demands. New approaches to integrate across these different scales are a promising avenue for better understanding how the brain functions. The first three papers in the issue address how networks change over the relatively slow time scales of development and aging. Keunen et al. explain the developmental changes that occur from the embryonic stage through early infancy and situate the development of functional brain networks within this framework. Prenatal and perinatal influences can affect the trajectory of network development, with lifelong consequences. The developmental trajectory is then picked up by Grayson and Fair, who discuss changes in both the structure and function of brain networks during the period from birth to adulthood. At the far end of the trajectory, Damoiseaux describes how aging impacts functional networks. There is evidence that the subtle but pervasive disruption of information flow through the brain that occurs over time is tied to alterations in the structural and functional connectivity in brain networks. In addition to the slow changes in functional connectivity that occur over a lifetime, more rapid processes can give rise to changes in connectivity over the course of a single scan. Preti et al. focus specifically on the temporal dynamics of functional networks elucidated with sliding window correlations and other time-resolved methods. Their manuscript addresses the proliferation of techniques used for dynamic analysis and helps researchers to make informed choices given both the promise and the challenges involved in this area. Characterizing the nature of functional connectivity dynamics is an intense research area and debate continues about whether these dynamics are neural in origin or attributable in some part to intrascan headmotion or physiological confounds. Lastly, Tagliazucchi and van Someren consider the dynamics of functional connectivity and functional networks during sleep and how this brings us further to understand the role of functional networks in arousal and conscious awareness. Functional brain connectivity is organized coherently across multiple spatial scales, ranging from the microscopic scale of synapses to the macroscopic networks commonly examined with noninvasive neuroimaging methodologies. At the macroscopic scale, taking a global view of functional connectivity, Liu et al. show that the global signal may provide functional information about the brain that is potentially different from the more localized information present in particular networks. Betzel and Bassett then review the organization of brain networks across different spatial, temporal, and topological levels, with topological scale here referring to the hierarchical subnetworks, modules and clubs into which a brain network can be decomposed using graph-theoretic models. Most current studies focus on a single scale; the relationship between scales remains at the frontier of neuroimaging research. One of the tools available to help neuroscientists understand how networks function at multiple scales is computational modeling. While neural mass and