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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 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. •The aging brain undergoes a complex functional reorganization process.•Age is related to decreases in within-network functional connectivity and to widespread increases and decreases in (anti-)correlations between different networks.•This study forms a basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease.

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Klinefelter syndrome (KS) is a genetic syndrome characterized by the presence of an extra X chromosome that appears to increase the risk of psychopathology, such as autism symptoms. This study used functional magnetic resonance imaging to determine underlying mechanisms related to this risk, with the aim of gaining insight into neural mechanisms behind social-cognitive dysfunction in KS and autism, and understanding similarities and differences in social information processing deficits. Fourteen boys with KS, seventeen boys with autism spectrum disorders (ASD) and nineteen non-clinical male controls aged 10–18 years were scanned while matching and labeling facial expressions (i.e. face processing and affect labeling, respectively). No group differences in neural activation were found during face processing. However, during affect labeling, the ASD group showed increased activation in the amygdala compared with controls, while the KS group showed increased activation in frontal areas compared with both controls and the ASD group. No group differences in task performance were found. Although behavioral symptoms of social dysfunction appear similar both in boys with KS and ASD, this is the first study to demonstrate different underlying etiologies. These results may aid in identifying different pathways to autism symptoms, which may help understanding variability within the ASD spectrum.

Neurobiological and behavioral findings suggest that the development of delinquent behavior is associated with atypical social-affective processing. However, to date, no study has examined neural processes associated with social interactions in severely antisocial adolescents. In this study we investigated the behavioral and neural processes underlying social interactions of juvenile delinquents and a matched control group. Participants played the mini-Ultimatum Game as a responder while in the MRI scanner. Participants rejected unfair offers significantly less when the other player had ‘no alternative’ compared with a ‘fair’ alternative, suggesting that they took the intentions of the other player into account. However, this effect was reduced in the juvenile delinquents. The neuroimaging results revealed that juvenile delinquents showed less activation in the temporal parietal junction (TPJ) and inferior frontal gyrus (IFG). However, the groups showed similar activation levels in the dorsal anterior cingulate cortex (dACC) and the right anterior insula (AI) when norms were violated. These results indicate that juvenile delinquents with severe antisocial behavior process norm violations adequately, but may have difficulties with attending spontaneously to relevant features of the social context during interactions.

We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research.

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 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. •We calculated resting state fMRI measures for Alzheimer patients and controls.•The resting state measures were used in elastic net classification analyses.•Functional connectivity and functional connectivity dynamics perform best.•Classification performance improves slightly when combining all measures.

Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data. 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions. We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

Subjective cognitive decline, a perceived worsening of cognitive functioning without objective deficit on assessment, could indicate incipient dementia. However, the neural correlates of subjective cognitive decline as assessed by magnetic resonance imaging remain somewhat unclear. Here, we evaluated differences in functional connectivity across memory regions, and cognitive performance, between healthy older adults aged 50 to 85 with (n = 35, Age = 68.5 ± 7.7, 22 female), and without (n = 48, Age = 67.0 ± 8.8, 29 female) subjective cognitive decline. We also evaluated neurite density, fractional anisotropy, and mean diffusivity of the parahippocampal cingulum, cingulate gyrus cingulum, and uncinate fiber bundles in a subsample of participants (n = 37). Participants with subjective cognitive decline displayed lower average functional connectivity across regions of a putative posterior memory system, and lower retrosplenial-precuneus functional connectivity specifically, than those without memory complaints. Furthermore, participants with subjective cognitive decline performed poorer than controls 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 subjective cognitive decline that could indicate potential incipient dementia. •Lower posterior memory system connectivity in subjective cognitive decline.•No group differences in anterior memory system connectivity.•Lower visual working memory performance in subjective cognitive decline.•No group differences in uncinate or cingulum diffusion measures.

Disruption 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 × 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.

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.