Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness... Show moreDisruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group x treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline. Show less
Klaassens, B.L.; Gerven, J.M.A. van; Klaassen, E.S.; Grond, J. van der; Rombouts, S.A.R.B. 2019
Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness... Show moreDisruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group x treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline. Show less
Klaassens, B.L.; Van Gerven, J.M.A.; Klaassen, E.S.; Van der Grond, J.; Rombouts, S.A.R.B. 2019
Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are... Show moreStructural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease. Show less
Subjective cognitive decline, a perceived worsening of cognitive functioning without objective deficit onassessment, could indicate incipient dementia. However, the neural correlates of subjective... Show moreSubjective cognitive decline, a perceived worsening of cognitive functioning without objective deficit onassessment, could indicate incipient dementia. However, the neural correlates of subjective cognitive decline asassessed by magnetic resonance imaging remain somewhat unclear. Here, we evaluated differences in functionalconnectivity across memory regions, and cognitive performance, between healthy older adults aged 50 to 85 with(n¼35,Age¼68.57.7, 22 female), and without (n¼48,Age¼67.08.8, 29 female) subjective cognitivedecline. We also evaluated neurite density, fractional anisotropy, and mean diffusivity of the parahippocampalcingulum, cingulate gyrus cingulum, and uncinatefiber bundles in a subsample of participants (n¼37). Partic-ipants with subjective cognitive decline displayed lower average functional connectivity across regions of a pu-tative posterior memory system, and lower retrosplenial-precuneus functional connectivity specifically, than thosewithout memory complaints. Furthermore, participants with subjective cognitive decline performed poorer thancontrols on visual working memory. However, groups did not differ in cingulum or uncinate diffusion measures.Our results show differences in functional connectivity and visual working memory in participants with subjectivecognitive decline that could indicate potential incipient dementia. Show less
Klaassens, B.L.; Gerven, J.M.A. van; Klaassen, E.S.; Grond, J. van der; Rombouts, S.A.R.B. 2018
Aging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with... Show moreAging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with resting state functional magnetic resonance imaging (RS-fMRI) in young and older adults. The instant response to the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study. A powerful dataset consisting of 522 RS-fMRI scans was obtained by acquiring multiple scans per subject before and after drug administration. Group x treatment interaction effects on voxelwise connectivity with ten functional networks were investigated (p < .05, FWE-corrected) using a non-parametric multivariate analysis technique with cerebrospinal fluid, white matter, heart rate and baseline measurements as covariates. Both groups showed a decrease in sensorimotor network connectivity after citalopram administration. The comparable findings after citalopram intake are possibly due to relatively similar serotonergic systems in the young and older subjects. Galantamine altered connectivity between the occipital visual network and regions that are implicated in learning and memory in the young subjects. The lack of a cholinergic response in the elderly might relate to the well-known association between cognitive and cholinergic deterioration at older age. Show less
Vos, F. de; Koini, M.; Schouten, T.M.; Seiler, S.; Grond, J. van der; Lechner, A.; ... ; Rombouts, S.A.R.B. 2018
Alzheimer's disease (AD) patients show altered patterns of functional connectivity (FC) on resting state functional magnetic resonance imaging (RSfMRI) scans. It is yet unclear which RSfMRI... Show moreAlzheimer's disease (AD) patients show altered patterns of functional connectivity (FC) on resting state functional magnetic resonance imaging (RSfMRI) scans. It is yet unclear which RSfMRI measures are most informative for the individual classification of AD patients. We investigated this using RSfMRI scans from 77 AD patients (MMSE = 20.4 ± 4.5) and 173 controls (MMSE = 27.5 ± 1.8). We calculated i) FC matrices between resting state components as obtained with independent component analysis (ICA), ii) the dynamics of these FC matrices using a sliding window approach, iii) the graph properties (e.g., connection degree, and clustering coefficient) of the FC matrices, and iv) we distinguished five FC states and administered how long each subject resided in each of these five states. Furthermore, for each voxel we calculated v) FC with 10 resting state networks using dual regression, vi) FC with the hippocampus, vii) eigenvector centrality, and viii) the amplitude of low frequency fluctuations (ALFF). These eight measures were used separately as predictors in an elastic net logistic regression, and combined in a group lasso logistic regression model. We calculated the area under the receiver operating characteristic curve plots (AUC) to determine classification performance. The AUC values ranged between 0.51 and 0.84 and the highest were found for the FC matrices (0.82), FC dynamics (0.84) and ALFF (0.82). The combination of all measures resulted in an AUC of 0.85. We show that it is possible to obtain moderate to good AD classification using RSfMRI scans. FC matrices, FC dynamics and ALFF are most discriminative and the combination of all the resting state measures improves classification accuracy slightly. Show less
Schouten, T.M.; Koini, M.; Vos, F. de; Seiler, S.; Rooij, M. de; Lechner, A.; ... ; Rombouts, S.A.R.B. 2017
Whereas we know a fair amount on the role of the amygdala in the acute stress response, virtually nothing is known about its role during the recovery period after the stress has waned. Functional... Show moreWhereas we know a fair amount on the role of the amygdala in the acute stress response, virtually nothing is known about its role during the recovery period after the stress has waned. Functional connectivity analysis of the amygdala during this period might be useful in revealing brain circuits promoting adaptive recovery from a stressful event, as well as consolidation of emotionally relevant information in preparing for future challenges. Healthy participants were randomly assigned to either a psychosocial stress task (n = 18; stress group) or a comparable non-stressful control procedure (n = 20; controls). To study the prolonged effects of stress on amygdala functional connectivity, resting-state fMRI scans were acquired an hour after the stress task. Amygdala functional connectivity with other brain regions was assessed using seed-based correlations. The stress group exhibited a strong physiological and behavioral reaction to psychosocial stress exposure. Compared with controls the stress group showed increased amygdala functional connectivity with three cortical midline structures: the posterior cingulate cortex and precuneus (p<.05, corrected), and the medial prefrontal cortex (p<.05, small volume corrected). An hour after psychosocial stress, changes in amygdala functional connectivity were detected with cortical midline structures involved in the processing and regulation of emotions, as well as autobiographical memory. It is hypothesized that these effects could relate to top-down control of the amygdala and consolidation of self-relevant information after a stressful event. These results on functional connectivity in the recovery phase after stress might provide an important new vantage point in studying both sensitivity and resilience to stress. (C) 2011 Elsevier Inc. All rights reserved. Show less
Guroglu, B.; Bos, W. van den; Dijk, E. van; Rombouts, S.A.R.B.; Crone, E.A. 2011
In this functional magnetic resonance imaging study, we examined developmental changes in the brain regions involved in reactions to unfair allocations. Previous studies on adults suggested that... Show moreIn this functional magnetic resonance imaging study, we examined developmental changes in the brain regions involved in reactions to unfair allocations. Previous studies on adults suggested that reactions to unfairness are not only affected by the distribution itself but also by the ascribed intentionality of the proposer. In the current study, we employed the mini Ultimatum Game (Falk, Fehr, & Fischbacher, 2003) to examine responder behavior to unfair offers of varying degrees of intentionality. Sixty-eight participants from four age groups (10-, 13-, 15-, and 20-year-olds) carried out the task while fMRI data were acquired. Participants of all ages showed activation in the bilateral insula and dorsal anterior cingulate cortex (dACC) during rejection of unintentional but acceptance of intentional unfair offers. Rejection of unintentional unfair offers further involved increasing activation with age in the temporoparietal junction and the dorsolateral prefrontal cortex. These findings provide evidence for an early developing insula-dACC network involved in detecting personal norm-violations and gradually increasing involvement of temporal and prefrontal brain regions related to intentionality considerations in social reasoning. The results are discussed in light of recent findings on the development of the adolescent social brain network. (C) 2011 Elsevier Inc. All rights reserved. Show less
Ferrarini, L.; Veer, I.M.; Lew, B. van; Oei, N.Y.L.; Buchem, M.A. van; Reiber, J.H.C.; ... ; Milles, J. 2011
In recent years, graph theory has been successfully applied to study functional and anatomical connectivity networks in the human brain. Most of these networks have shown small-world topological... Show moreIn recent years, graph theory has been successfully applied to study functional and anatomical connectivity networks in the human brain. Most of these networks have shown small-world topological characteristics: high efficiency in long distance communication between nodes, combined with highly interconnected local clusters of nodes. Moreover. functional studies performed at high resolutions have presented convincing evidence that resting-state functional connectivity networks exhibits (exponentially truncated) scale-free behavior. Such evidence, however. was mostly presented qualitatively, in terms of linear regressions of the degree distributions on log-log plots. Even when quantitative measures were given, these were usually limited to the r(2) correlation coefficient. However, the r2 statistic is not an optimal estimator of explained variance, when dealing with (truncated) power-law models. Recent developments in statistics have introduced new non-parametric approaches. based on the Kolmogorov-Smirnov test, for the problem of model selection. In this work, we have built on this idea to statistically tackle the issue of model selection for the degree distribution of functional connectivity at rest. The analysis, performed at voxel level and in a subject-specific fashion, confirmed the superiority of a truncated power-law model, showing high consistency across subjects. Moreover, the most highly connected voxels were found to be consistently part of the default mode network. Our results provide statistically sound support to the evidence previously presented in literature for a truncated power-law model of resting-state functional connectivity. (C) 2011 Elsevier Inc. All rights reserved. Show less
Several studies have examined the neural effects of working memory practice, but due to different task demands, diverse patterns of neural changes have been reported. In the present study, we... Show moreSeveral studies have examined the neural effects of working memory practice, but due to different task demands, diverse patterns of neural changes have been reported. In the present study, we examined neural effects of practice using a task with different working memory demands within a single practice paradigm. Fifteen adults practiced during 6 weeks with a task that required maintenance and manipulation of information under low and high working memory loads. Functional magnetic resonance imaging (FMRI) data were acquired in the first week and last week of the practice period. Results were compared with results of a control group who did not practice the task. We demonstrated that practice was beneficial for both working memory maintenance and manipulation processes but that these processes were supported by different neural changes. While maintenance trials showed increased activation (i.e., less deactivation) in default-mode regions after practice, manipulation trials experienced increased activation in the striatum. Changes were also observed in left ventrolateral prefrontal cortex (VLPFC), bilateral dorsolateral prefrontal cortex (DLPFC) and left superior parietal cortex (SPC). However, for bilateral DLPFC and left SPC, these changes were not specific to the practice group. These findings illustrate the importance of controlling for test-retest effects in training or intervention studies. Behavioral follow-up tests demonstrated that practice effects lasted over a 6-month period, but the absence of transfer effects indicated that the acquired skills were specific for the practiced working memory task. (C) 2010 Elsevier Inc. All rights reserved. Show less
