Serotonin transporter occupancy by the SSRI citalopram predicts default-mode network connectivity

Unprecedented 4D spatiotemporal infant regional cerebral blood flow framework and region-specific physiology–function coupling across infancy were elucidated, highlighting strong physiology–function coupling specifically at the default-mode network to meet extraneuronal metabolic demand for network emergence.

Objective: To study resting-state functional connectivity (FC) of default mode network (DMN) in adolescent patients with first-episode drug-naive major depressive disorder (MDD). Methods: We enrolled thirty first-episode and drug-naive adolescent MDD patients and twenty-nine adolescent healthy control (HC) participants in the First Affiliated Hospital of Zhengzhou University. There were no differences in age, sex, and education between the MDD and HC group. Resting-state functional magnetic resonance images (fMRI) was performed. We selected posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) of DMN as regions of interests (ROI). The differences of these regions from the whole brain functional connectivity were analyzed. The relations between abnormalities in FCs of DMN and clinical variables were further investigated. Results: Compared to the HCs, the MDD patients had congruently reduced FCs between the PCC and cerebellum, temporal cortices, occipital cortices, fusiform, dorsolateral prefrontal cortex. MPFC not only had reduced FCs with fusiform, temporal cortices, anterior cingulate cortex, but also had enhanced FCs with occipital cortices, parietal cortices, and precentral gyrus. In addition, the increased FC between the right MPFC and right precentral gyrus was positive correlated with Hamilton Rating Scale for Depression (HAMD) scores (r=0.38, P=0.04). The reduced FC between the left middle temporal gyrus and left PCC as well as the enhanced FC between the right middle cingulum and right MPFC were positive correlated with the duration of depression since onset (r=0.39, P=0.03; r=0.38, P=0.04). Conclusions: These findings show dysfunctional DMN connectivity of adolescent MDD patients. Neurodevelopmental abnormalities in DMN may present in adolescent MDD.

IntroductionObstructive sleep apnea (OSA)‐associated hypoxemia, sleep fragmentation, and cerebral vascular dysfunction are implicated in cognitive dysfunction. Functional connectivity within default mode network (DMN) is a possible mechanism underlying the cognitive impairment. The aim of this study was to investigate the impact of hypoxemia and sleep fragmentation on functional connectivity and on cognitive performance in patients with OSA.MethodsTwenty‐eight patients with OSA were included (mean age = 58.0 ± 8.5 years). We correlated the functional connectivity in DMN with cognitive performances and further analyzed the relationship of functional connectivity in DMN with hypoxemia severity, as revealed by apnea‐hypopnea index (AHI), oxygen desaturation index (ODI), and nadir SaO2 (%), and with degree of sleep fragmentation, as shown by sleep efficiency and wake after sleep onset.ResultsFunctional connectivity in DMN was associated with AHI, ODI, and nadir SaO2 (%) (p < .05) and was not associated with sleep fragmentation measures (p > .05). Functional connectivity that was associated with AHI, ODI, and nadir SaO2 (%) was in the areas of bilateral middle temporal gyri, bilateral frontal pole, and bilateral hippocampus and was positively correlated with Cognitive Abilities Screening Instrument (CASI) total score (ρ = 0.484; p = .012), CASI‐List‐generating, CASI‐Attention, and composite score of CASI‐List‐generating plus CASI‐Attention (p < .05).ConclusionFunctional connectivity in DMN is implicated in impairment of global cognitive function and of attention in OSA patients. The functional connectivity in the DMN is associated with hypoxemia rather than with sleep fragmentation.

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.

Some people can easily empathize with others, while others cannot. The neural mechanism underlying individual difference of how much people can empathize with others is still not clear. Vicarious reward is the phenomenon by which we vicariously experience the positive sensations or emotions of others. Beta oscillatory activity (BOA) is observed when participants experience vicarious reward. Recent studies have reported that the default mode network (DMN) is also involved in reward processing and have suggested that individual differences in the way participants respond to reward stimuli are correlated with DMN functional connectivity during the resting state. In the current study, we investigated whether DMN functional connectivity during the resting state is also correlated with BOA for vicarious reward. Participants watched a player playing a game (Kendama) and investigated the correlation of BOA amplitude and resting state DMN functional connectivity. The results revealed a significant correlation between the degree of phase synchronization within DMN components in the resting state and the amplitude of BOA while participants experienced vicarious reward. The results suggested that functional connectivity within the DMN in the resting state positively influenced vicarious reward processing while observing others receiving a reward.

Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.

Women show an increased lifetime risk of Alzheimer's disease (AD) compared with men. Characteristic brain connectivity changes, particularly within the default mode network (DMN), have been associated with both symptomatic and preclinical AD, but the impact of sex on DMN function throughout aging is poorly understood. We investigated sex differences in DMN connectivity over the lifespan in 595 cognitively healthy participants from the Human Connectome Project-Aging cohort. We used the intrinsic connectivity distribution (a robust voxel-based metric of functional connectivity) and a seed connectivity approach to determine sex differences within the DMN and between the DMN and whole brain. Compared with men, women demonstrated higher connectivity with age in posterior DMN nodes and lower connectivity in the medial prefrontal cortex. Differences were most prominent in the decades surrounding menopause. Seed-based analysis revealed higher connectivity in women from the posterior cingulate to angular gyrus, which correlated with neuropsychological measures of declarative memory, and hippocampus. Taken together, we show significant sex differences in DMN subnetworks over the lifespan, including patterns in aging women that resemble changes previously seen in preclinical AD. These findings highlight the importance of considering sex in neuroimaging studies of aging and neurodegeneration.

The structural connectivity patterns of human brain are the underlying basis of functional connectivity.Abnormal functional connectivity in default mode network(DMN) has been uncovered in electroencephalography(EEG) and functional magnetic resonance imaging(fMRI) studies,which suggests that the abnormality might be related to the cognitive mental impairment and unconsciousness during absence seizures.However,so far,little is known about the structural connectivity in DMN about childhood absence epilepsy(CAE).In the present study,we hypothesize that the structural connectivity in DMN should be disrupted to respond to the altered brain function in CAE.To test the hypothesis,11 patients with CAE and 12 age-and gender-matched healthy controls were recruited.We utilized diffusion tensor imaging tractography to map the anatomical structural connectivity of DMN.The fiber bundles among regions of DMN were built for each subject.Then,mean length,fractional anisotropic(FA),mean diffusivity(MD) and connection strength on fibers linking two brain regions were calculated.Further,these parameters were executed two-sample t-test between CAE group and health control group.Finally,we used Pearson's correlation coefficient to evaluate the relationship between these parameters and epilepsy duration(year).Both CAE and healthy control groups showed similar structural connectivity patterns in DMN.Among these fiber bundles,three were identified in all subjects,with one linking posterior cingulate cortex/precuneus to medial prefrontal cortex,and another two linking posterior cingulate cortex/precuneus to bilateral medial temporal lobes.Furthermore,the significantly decreased FA and connection strength,and increased MD in fiber bundles linking posterior cingulated cortex/precuneus to medial prefrontal cortex,were found in patients compared with the cases in healthy controls(P 0.05,Bonferroni corrected).Predominantly,the FA values in fiber bundles linking posterior cingulated cortex/precuneus to medial prefrontal cortex were negatively correlated with the epilepsy duration(P=0.006).These findings might reflect the structural basis of the altered functional connectivity in DMN about absence epilepsy.Given that functional connectivity abnormality in our previous work,it is implied that the abnormal fiber connectivity from posterior cingulated cortex/precuneus to medial prefrontal cortex plays an important role in absence epilepsy.This may open up new avenues to understand the pathophysiological mechanisms of absence epilepsy.

Emotional empathy is the ability to experience and/or share another person’s emotional states and responses. Although some research has examined the neural correlates of emotional empathy, there has been little research investigating whether this component of empathy is related to the functional connectivity of resting state networks in the brain. In the current study, 32 participants answered a trait emotional empathy questionnaire in a session previous to their functional magnetic resonance imaging scan. Results indicate that emotional empathy scores were correlated with different patterns of functional connectivity in the default mode network (DMN), salience network (SN), and left and right central executive networks. For example, within the DMN, emotional empathy scores positively correlated with connectivity in the premotor cortex. Within the SN, empathy scores were positively correlated with the fusiform gyrus and cuneus. These findings demonstrate that emotional empathy is associated with unique patterns of functional connectivity in four of the brain’s resting state networks.

Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer’s Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60–90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.

BackgroundNeurofilament light (NfL) is a measure of neuronal damage and has the potential as a monitoring and prognostic biomarker of Alzheimer’s disease (AD) (Mattsson et al., 2019). Likewise, alterations in default mode network (DMN) functional connectivity (FC) may predict AD progression (Jones et al., 2016). Here, we investigated the relationship between plasma NfL levels and DMN FC along the continuum of AD, and explored whether APOE ε4 status influenced this relationship.MethodResting‐state functional MRI data and blood samples were available for 103 older adults (17 with AD dementia, age: 69.2±6.9; m/f: 8/9; CDR: 0.7±0.3; and 86 without dementia (includes amnestic MCI and control), age: 71.7±7.4; m/f: 21/65; CDR: 0.3±0.2). Plasma NfL was measured using a single‐molecule array (Simoa) assay. We calculated DMN FC using 32 high consensus DMN ROIs from Dworetsky et al. (2021). DMN FC was defined as the average correlation between the mean time‐series of three ROIs labeled as posterior cingulate cortex and those of all the other ROIs. Participants’ APOE status was defined as APOE ε4 carriers (ε3/ε4 or ε4/ε4) and noncarriers (ε3/ε3). Multiple regression was run with DMN FC as the outcome variable, plasma NfL as the predictor, and age and sex as covariates.ResultPlasma NfL levels were higher in those with dementia compared to those without dementia (t = 4.4608, p = 0.0002) but did not differ between amnestic MCI and control (t = 1.6116, p = 0.1130). Across all participants, plasma NfL did not predict DMN FC (Β = 0.0045, p = 0.4830). However, higher plasma NfL was marginally associated with higher DMN FC in those with dementia (Β = 0.0045, p = 0.0657) but not in those without dementia (Β = 0.0021, p = 0.3160). Moreover, in those without dementia, higher plasma NfL predicted higher DMN FC in APOE ε4 carriers (Β = 0.0079, p = 0.0312) but not in APOE ε4 noncarriers (Β = 0.0023, p = 0.4871).ConclusionOur results indicate that the increase of DMN FC, seen at early stages of AD (Damoiseaux et al., 2012), is significantly associated with more neuronal damage in APOE ε4 carriers without dementia.

Reports an error in "Default mode functional connectivity is associated with social functioning in schizophrenia" by Jaclyn M. Fox, Samantha V. Abram, James L. Reilly, Shaun Eack, Morris B. Goldman, John G. Csernansky, Lei Wang and Matthew J. Smith (Journal of Abnormal Psychology, 2017[May], Vol 126[4], 392-405). In the article, the email address of corresponding author Matthew J. Smith was set as matthewsmith@northwestern.edu. It should have been mattjsmi@umich.edu. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-14073-001.) Individuals with schizophrenia display notable deficits in social functioning. Research indicates that neural connectivity within the default mode network (DMN) is related to social cognition and social functioning in healthy and clinical populations. However, the association between DMN connectivity, social cognition, and social functioning has not been studied in schizophrenia. For the present study, the authors used resting-state neuroimaging data to evaluate connectivity between the main DMN hubs (i.e., the medial prefrontal cortex [mPFC] and the posterior cingulate cortex-anterior precuneus [PPC]) in individuals with schizophrenia (n = 28) and controls (n = 32). The authors also examined whether DMN connectivity was associated with social functioning via social attainment (measured by the Specific Levels of Functioning Scale) and social competence (measured by the Social Skills Performance Assessment), and if social cognition mediates the association between DMN connectivity and these measures of social functioning. Results revealed that DMN connectivity did not differ between individuals with schizophrenia and controls. However, connectivity between the mPFC and PCC hubs was significantly associated with social competence and social attainment in individuals with schizophrenia but not in controls as reflected by a significant group-by-connectivity interaction. Social cognition did not mediate the association between DMN connectivity and social functioning in individuals with schizophrenia. The findings suggest that fronto-parietal DMN connectivity in particular may be differentially associated with social functioning in schizophrenia and controls. As a result, DMN connectivity may be used as a neuroimaging marker to monitor treatment response or as a potential target for interventions that aim to enhance social functioning in schizophrenia. (PsycINFO Database Record

BackgroundSubcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. White matter hyperintensities (WMH) secondary to SIVCI often result in impaired executive function. Cognitive reserve is a property of the brain that allows for preserved cognitive performance given brain injury or disease. In an unpublished cross‐sectional study, we found the strength of intra‐network connectivity in fronto‐executive network (FEN), fronto‐parietal network (FPN) and default mode network (DMN) moderated the relationship between WMH and executive function in older adults with SIVCI. Thus, these networks may be involved in cognitive reserve. Exercise is hypothesized to contribute to cognitive reserve. We explored the effect of resistance training (RT) on functional connectivity (FC) in FEN, FPN, and DMN, as well as executive function, in older adults with SIVCI.MethodIn a 12‐month randomized controlled trial that randomized adults with SIVCI to either 2x/week of RT or 2x/week of balance and tone training (BAT; control). Resting‐state functional MRI was collected from a subset of 29 participants (RT = 14; BAT = 15) at baseline and trial completion. FC of FEN, FPN, and DMN was quantified using priori‐selected region‐of‐interest masks. Executive function was measured by Trail Making Test (TMT), Digit Symbol Substitution Test (DSST) and Stroop Test (ST). Analysis of covariance was conducted to compare differences in group means of intra‐network FC of FEN, FPN and DMN and executive function tests performance at trial completion, with baseline outcome scores as covariate. Pearson correlations were computed to determine whether changes in executive performance between baseline and trial completion were related to changes in FC in the RT group.ResultAt trial completion, there were no significant between‐group differences in intra‐network FC of FEN, FPN and DMN. RT significantly improved ST performance (estimated mean change[95%CI]: ‐11.322[‐22.366, ‐0.277], p = 0.045) compared with BAT; there were no significant between‐group differences in TMT and DSST. Within RT group, improved ST performance was significantly correlated with increased intra‐network FC of FEN (r = ‐0.697, p = 0.006).ConclusionRT‐induced improvement in ST performance was associated with increased intra‐network FC of FEN. More research is needed to determine whether exercise training has an effect on the neural correlates of cognitive reserve.

Fatigue is a common problem in PD either in the early or later stage of the disease. Using resting-state functional MRI, we investigated the functional correlates of fatigue in a cohort of "drug-naïve" patients with PD. MRI at 3Tesla was collected in 40 patients with PD, 20 with and 20 without fatigue, and 20 matched healthy controls. Presence and the severity of fatigue were defined based on the 16-item Parkinson fatigue scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting state networks between patients subgroups and healthy controls. In addition, we used voxel-based morphometry to test whether between-group functional changes were related to structural differences. Distressing fatigue was associated with a decreased connectivity in the supplementary motor area within the sensorimotor network and an increased connectivity in the prefrontal and posterior cingulate cortices within the default mode network (P < 0.05 corrected). Fatigue severity was correlated with both sensorimotor and default mode networks connectivity changes. Voxel-based morphometry analysis did not reveal any significant volume differences between all patients with PD and healthy controls and between patients with PD with and without fatigue (P < 0.05; family-wise error). Our findings revealed that primary PD-related fatigue is associated with an altered default mode network and sensorimotor network connectivity in drug-naïve patients. We hypothesize that these divergent motor and cognitive networks connectivity changes and their adaptive or maladaptive functional outcome may play a prominent role in the pathophysiology of fatigue in PD. © 2016 International Parkinson and Movement Disorder Society.

Default mode network alterations in individuals with high-trait-anxiety: An EEG functional connectivity study.