Remco Renken

Regional brain volume in depression and anxiety disorders

CONTEXT Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN Cross-sectional study. SETTING Netherlands Study of Depression and Anxiety. PARTICIPANTS Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder.

Mapping the information flow from one brain to another during gestural communication

Both the putative mirror neuron system (pMNS) and the ventral medial prefrontal cortex (vmPFC) are deemed important for social interaction: the pMNS because it supposedly “resonates” with the actions of others, the vmPFC because it is involved in mentalizing. Strictly speaking, the resonance property of the pMNS has never been investigated. Classical functional MRI experiments have only investigated whether pMNS regions augment their activity when an action is seen or executed. Resonance, however, entails more than only “going on and off together”. Activity in the pMNS of an observer should continuously follow the more subtle changes over time in activity of the pMNS of the actor. Here we directly explore whether such resonance indeed occurs during continuous streams of actions. We let participants play the game of charades while we measured brain activity of both gesturer and guesser. We then applied a method to localize directed influences between the brains of the participants: between-brain Granger-causality mapping. Results show that a guessers brain activity in regions involved in mentalizing and mirroring echoes the temporal structure of a gesturers brain activity. This provides evidence for resonance theories and indicates a fine-grained temporal interplay between regions involved in motor planning and regions involved in thinking about the mental states of others. Furthermore, this method enables experiments to be more ecologically valid by providing the opportunity to leave social interaction unconstrained. This, in turn, would allow us to tap into the neural substrates of social deficits such as autism spectrum disorder.

Neuroticism modulates amygdala-prefrontal connectivity in response to negative emotional facial expressions

Neuroticism is associated with the experience of negative affect and the development of affective disorders. While evidence exists for a modulatory role of neuroticism on task induced brain activity, it is unknown how neuroticism affects brain connectivity, especially the crucial coupling between the amygdala and the prefrontal cortex. Here we investigate this relation between functional connectivity and personality in response to negative facial expressions. Sixty healthy control participants, from the Netherlands Study on Depression and Anxiety (NESDA), were scanned during an emotional faces gender decision task. Activity and functional amygdala connectivity (psycho-physiological interaction [PPI]) related to faces of negative emotional valence (angry, fearful and sad) was compared to neutral facial expressions, while neuroticism scores were entered as a regressor. Activity for fearful compared to neutral faces in the dorsomedial prefrontal (dmPFC) cortex was positively correlated with neuroticism scores. PPI analyses revealed that right amygdala-dmPFC connectivity for angry and fearful compared to neutral faces was positively correlated with neuroticism scores. In contrast, left amygdala-anterior cingulate cortex (ACC) connectivity for angry, fearful and sad compared to neutral faces was negatively related to neuroticism levels. DmPFC activity has frequently been associated with self-referential processing in social cognitive tasks. Our results therefore suggest that high neurotic participants display stronger self-referential processing in response to negative emotional faces. Second, in line with previous reports on ACC function, the negative correlation between amygdala-ACC connectivity and neuroticism scores might indicate that those high in neuroticism display diminished control function of the ACC over the amygdala. These connectivity patterns might be associated with vulnerability to developing affective disorders such as depression and anxiety.

A Brain-Wide Study of Age-Related Changes in Functional Connectivity

Aging affects functional connectivity between brain areas, however, a complete picture of how aging affects integration of information within and between functional networks is missing. We used complex network measures, derived from a brain-wide graph, to provide a comprehensive overview of age-related changes in functional connectivity. Functional connectivity in young and older participants was assessed during resting-state fMRI. The results show that aging has a large impact, not only on connectivity within functional networks but also on connectivity between the different functional networks in the brain. Brain networks in the elderly showed decreased modularity (less distinct functional networks) and decreased local efficiency. Connectivity decreased with age within networks supporting higher level cognitive functions, that is, within the default mode, cingulo-opercular and fronto-parietal control networks. Conversely, no changes in connectivity within the somatomotor and visual networks, networks implicated in primary information processing, were observed. Connectivity between these networks even increased with age. A brain-wide analysis approach of functional connectivity in the aging brain thus seems fundamental in understanding how age affects integration of information.

Hierarchical functional modularity in the resting‐state human brain

Functional magnetic resonance imaging (fMRI) studies have shown that anatomically distinct brain regions are functionally connected during the resting state. Basic topological properties in the brain functional connectivity (BFC) map have highlighted the BFCs small‐world topology. Modularity, a more advanced topological property, has been hypothesized to be evolutionary advantageous, contributing to adaptive aspects of anatomical and functional brain connectivity. However, current definitions of modularity for complex networks focus on nonoverlapping clusters, and are seriously limited by disregarding inclusive relationships. Therefore, BFCs modularity has been mainly qualitatively investigated. Here, we introduce a new definition of modularity, based on a recently improved clustering measurement, which overcomes limitations of previous definitions, and apply it to the study of BFC in resting state fMRI of 53 healthy subjects. Results show hierarchical functional modularity in the brain. Hum Brain Mapp, 2009.

Men Versus Women on Sexual Brain Function: Prominent Differences During Tactile Genital Stimulation, but not During Orgasm

Biological differences in male and female sexuality are obvious in the behavioral domain, but the central mechanisms that might explain these behavioral gender differences remain unclear. In this study, we merged two earlier positron emission tomography data sets to enable systematic comparison of the brain responses in heterosexual men and women during sexual tactile genital (penile and clitoral) stimulation and during orgasm. Gender commonalities were most evident during orgasm, a phase which demonstrated activations in the anterior lobe of the cerebellar vermis and deep cerebellar nuclei, and deactivations in the left ventromedial and orbitofrontal cortex in both men and women. During tactile genital stimulation, deactivations in the right amygdala and left fusiform gyrus were found for both genders. Marked gender differences were seen during this phase: left fronto‐parietal areas (motor cortices, somatosensory area 2 and posterior parietal cortex) were activated more in women, whereas in men, the right claustrum and ventral occipitotemporal cortex showed larger activation. The only prominent gender difference during orgasm was male‐biased activation of the periaqueductal gray matter. From these results, we conclude that during the sexual act, differential brain responses across genders are principally related to the stimulatory (plateau) phase and not to the orgasmic phase itself. These results add to a better understanding of the neural underpinnings of human sexuality, which might benefit treatment of psychosexual disorders. Hum Brain Mapp 2009.

The effect of intra- and inter-subject variability of hemodynamic responses on group level Granger causality analyses

Granger causality analyses aim to reveal the direction of influence between brain areas by analyzing temporal precedence: if a signal change in area A consistently precedes a signal change in area B, then A Granger-causes B. fMRI-based Granger causality inferences are mediated by the hemodynamic response function which can vary across brain regions. This variability might induce a bias in Granger causality analyses. Here we use simulations to investigate the effect of hemodynamic response variability on Granger causality analyses at the level of a group of twenty participants. We used a set of hemodynamic responses measured by Handwerker et al. (Neuroimage, 2004) and simulated 200 experiments in which time series with known directions of influence are convolved with these hemodynamic responses and submitted to Granger causality analysis. Results show that the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics. Most importantly, when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases. The sensitivity of the analyses however depended on the neuronal delay between the source and target regions and their relative hemodynamic delay. Influences flowing from regions to one with the same or a slower hemodynamic response function were detected in over 80% of the cases when the neuronal delay was at least 100 ms. Influences flowing to a region with a faster hemodynamic delay were detected in over 80% of the cases when delays are above 1s.

Reduced Specificity of Functional Connectivity in the Aging Brain During Task Performance

The importance of studying connectivity in the aging brain is increasingly recognized. Recent studies have shown that connectivity within the default mode network is reduced with age and have demonstrated a clear relation of these changes with cognitive functioning. However, research on age‐related changes in other functional networks is sparse and mainly focused on prespecified functional networks. Using functional magnetic resonance imaging, we investigated age‐related changes in functional connectivity during a visual oddball task in a range of functional networks. It was found that compared with young participants, elderly showed a decrease in connectivity between areas belonging to the same functional network. This was found in the default mode network and the somatomotor network. Moreover, in all identified networks, elderly showed increased connectivity between areas within these networks and areas belonging to different functional networks. Decreased connectivity within functional networks was related to poorer cognitive functioning in elderly. The results were interpreted as a decrease in the specificity of functional networks in older participants. Hum Brain Mapp 35:319–330, 2014.

Group analyses of connectivity-based cortical parcellation using repeated k-means clustering

K-means clustering has become a popular tool for connectivity-based cortical segmentation using Diffusion Weighted Imaging (DWI) data. A sometimes ignored issue is, however, that the output of the algorithm depends on the initial placement of starting points, and that different sets of starting points therefore could lead to different solutions. In this study we explore this issue. We apply k-means clustering a thousand times to the same DWI dataset collected in 10 individuals to segment two brain regions: the SMA-preSMA on the medial wall, and the insula. At the level of single subjects, we found that in both brain regions, repeatedly applying k-means indeed often leads to a variety of rather different cortical based parcellations. By assessing the similarity and frequency of these different solutions, we show that approximately 256 k-means repetitions are needed to accurately estimate the distribution of possible solutions. Using nonparametric group statistics, we then propose a method to employ the variability of clustering solutions to assess the reliability with which certain voxels can be attributed to a particular cluster. In addition, we show that the proportion of voxels that can be attributed significantly to either cluster in the SMA and preSMA is relatively higher than in the insula and discuss how this difference may relate to differences in the anatomy of these regions.

Cerebral activation during motor imagery in complex regional pain syndrome type 1 with dystonia.

&NA; The pathogenesis of dystonia in Complex Regional Pain Syndrome type 1 (CRPS‐1) is unclear. In primary dystonia, functional magnetic resonance imaging (fMRI) has revealed changes in cerebral networks during execution of movement. The aim of this study was to determine cerebral network function in CRPS‐1 patients with dystonic postures. Cerebral processing related to both execution and imagining of hand movements in patients and controls was assessed with fMRI. Eight CRPS‐1 patients with dystonic postures of the right upper extremity and 17 age‐matched healthy controls were studied. Compared with controls, imaginary movement of the affected hand in patients showed reduced activation ipsilaterally in the premotor and adjacent prefrontal cortex, and in a cluster comprising frontal operculum, the anterior part of the insular cortex and the superior temporal gyrus. Contralaterally, reduced activation was seen in the inferior parietal and adjacent primary sensory cortex. There were no differences between patients and controls when they executed movements, nor when they imagined moving their unaffected hand. The altered cerebral activation pattern in patients with CRPS‐1 linked dystonia most likely reflects an interface between pain‐associated circuitry and higher order motor control, which points at a specific mechanistic pathophysiology of this type of dystonia.