Default Mode Network Functional Connectivity Research Articles

Depression Is Associated with the Aberration of Resting State Default Mode Network Functional Connectivity in Patients with Amyloid-Positive Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia, and a significant number of individuals with MCI progress to develop dementia. Depression is prevalent in MCI patients and has been found to influence the disease progression of MCI. The default mode network (DMN), a brain network associated with Alzheimer's disease (AD), and its functional connectivity might be a neurological mechanism linking depression and AD. However, the relationship between depression, DMN functional connectivity, and cerebral beta-amyloid (Aβ) pathology remains unclear. This study aimed to investigate DMN functional connectivity differences in Aβ-positive MCI patients with depression compared to those without depression. A total of 126 Aβ-positive MCI patients were included, with 66 having depression and 60 without depression. The results revealed increased functional connectivity in the anterior DMN in the depression group compared to the non-depression group. The functional connectivity of the anterior DMN positively correlated with depression severity but not with Aβ deposition. Our findings suggest that depression influences DMN functional connectivity in Aβ-positive MCI patients, and the depression-associated DMN functional connectivity aberrance might be an important neural mechanism linking depression, Aβ pathology, and disease progression in the trajectory of AD.

The mediating role of default mode network during meaning-making aroused by mental simulation between stressful events and stress-related growth: a task fMRI study

BackgroundStressful events and meaning-making toward them play an important role in adolescents’ life and growth. However, ignoring positive stressful events leads to negativity bias; further, the neural mechanisms of meaning-making are unclear. We aimed to verify the mediating role of meaning-making in stressful events and stress-related growth and the function of the default mode network (DMN) during meaning-making in this functional magnetic resonance imaging (fMRI) study.MethodsParticipants comprised 59 university students. Stressful life events, meaning-making, and stress-related growth were assessed at baseline, followed by fMRI scanning during a meaning-making task aroused by mental simulation. General linear modeling and psychophysiological interaction (PPI) analyses were used to explore the activation and functional connectivity of DMN during meaning-making.ResultsMental simulation triggered meaning-making, and DMN activity decreased during meaning-making. Activation of the DMN was negatively correlated with coping flexibility, an indicator of stress-related growth. PPI analysis showed that meaning-making was accompanied by diminished connectivity in the DMN. DMN activation during meaning-making can mediate the relationship between positive stressful events and coping flexibility.ConclusionsDecreased DMN activity and diminished functional connectivity in the DMN occurred during meaning-making. Activation of the DMN during meaning-making could mediate the relationship between positive stressful events and stress-related growth, which provides a cognitive neural basis for the mediating role of meaning-making in the relationship between stressful events and indicators of stress-related growth.ImplicationsThis study supports the idea that prosperity makes heroes, expands the meaning-making model, and suggests the inclusion of enhancing personal resources and meaning-making in education. This study was the first to validate the activation pattern and functional connectivity of the DMN during meaning-making aroused by mental simulation using an fMRI task-state examination, which can enhance our sense of meaning and provide knowledge that can be used in clinical psychology interventions.Trial RegistrationThe study protocol was pre-registered in Open Science Framework (see osf.io/ahm6e for details).

Psychological resilience mediates the protective role of default-mode network functional connectivity against COVID-19 vicarious traumatization

Vicarious traumatization (VT), a negative reaction to witnessing others’ trauma, has been experienced by some people during the COVID-19 pandemic, and can lead to mental health problems. This study aimed to identify functional brain markers of COVID-specific VT and explore the psychological mechanism underlying the brain-VT link. One hundred healthy participants underwent resting-state functional magnetic resonance imaging before the pandemic (October 2019–January 2020) and completed VT measurement during the pandemic (February–April 2020). Whole-brain correlation analysis based on global functional connectivity density (FCD) mapping revealed that VT was negatively correlated with FCD in the right inferior temporal gyrus (ITG) (i.e., the lower FCD in ITG, the worse the VT), identified by mapping onto known large-scale networks as part of the default-mode network (DMN). Resting-state functional connectivity (RSFC) analysis using ITG as seed found that VT was predicted by lower functional connectivity between ITG and other DMN regions including left medial prefrontal cortex, left orbitofrontal cortex, right superior frontal gyrus, right inferior parietal lobule and bilateral precuneus (i.e., the lower the ITG-DMN connectivity, the worse the VT). Mediation analyses suggested that psychological resilience served as a mediator in these associations of ITG FCD and ITG-DMN RSFC with VT. Our results provide novel evidence on the brain basis of VT and emphasize psychological resilience as an important link from DMN functional connectivity to COVID-specific-VT. This may facilitate public health interventions by helping identify individuals at risk of stress- and trauma-related psychopathologies.

Effects of spaceflight on the EEG alpha power and functional connectivity

Electroencephalography (EEG) can detect changes in cerebral activity during spaceflight. This study evaluates the effect of spaceflight on brain networks through analysis of the Default Mode Network (DMN)'s alpha frequency band power and functional connectivity (FC), and the persistence of these changes. Five astronauts' resting state EEGs under three conditions were analyzed (pre-flight, in-flight, and post-flight). DMN’s alpha band power and FC were computed using eLORETA and phase-locking value. Eyes-opened (EO) and eyes-closed (EC) conditions were differentiated. We found a DMN alpha band power reduction during in-flight (EC: p < 0.001; EO: p < 0.05) and post-flight (EC: p < 0.001; EO: p < 0.01) when compared to pre-flight condition. FC strength decreased during in-flight (EC: p < 0.01; EO: p < 0.01) and post-flight (EC: ns; EO: p < 0.01) compared to pre-flight condition. The DMN alpha band power and FC strength reduction persisted until 20 days after landing. Spaceflight caused electrocerebral alterations that persisted after return to earth. Periodic assessment by EEG-derived DMN analysis has the potential to become a neurophysiologic marker of cerebral functional integrity during exploration missions to space.

Differential associations between plasma neurofilament light and brain functional connectivity in patients with Alzheimer’s disease and fronto‐temporal dementia

AbstractBackgroundNeurofilament light chain (NfL), a marker of axonal loss, is elevated in both Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD)[1‐6]. AD and bvFTD have been shown to spread along specific networks reflective of their symptom profiles[7,8], with AD associated with declines in default mode network (DMN) functional connectivity (FC), and bvFTD linked to disruptions in salience network (SN) FC[9]. However, the association between plasma NfL and FC in these two groups remains unknown. Given evidence linking plasma NfL to hypometabolism in circumscribed regions within the DMN in mild cognitive impairment (MCI) patients[10], we hypothesize that NfL would similarly be associated with FC in a network‐specific manner in AD and bvFTD.MethodPlasma NfL and neuroimaging data from young‐onset patients with bvFTD (n = 16) and AD (n = 38; including AD and MCI of AD type (AD+MCI)) were analyzed. Plasma NfL was measured by single molecule array (SIMOA). Seed‐based FC maps using regions‐of‐interest from DMN (left posterior cingulate cortex) and SN (right anterior insula) were derived for each patient. Voxelwise analyses examining associations between plasma NfL and seed‐based FC were first performed in each group separately. Clusters showing significant FC‐NfL associations were then examined for group differences between AD+MCI and bvFTD, and correlated with neuropsychological performance. All analyses accounted for age, sex, education, handedness and total intracranial volumes.ResultsWe demonstrated differential associations between plasma NfL and FC in AD+MCI and bvFTD patients: AD+MCI patients showed significantly lower DMN FC with higher plasma NfL compared to bvFTD patients (Figure 1A), while bvFTD patients showed lower SN FC (Figure 1B) with higher plasma NfL relative to AD+MCI patients. Further, lower NfL‐related DMN FC in AD+MCI patients was significantly associated with lower MoCA scores (Figure 2).ConclusionPlasma NfL is associated with FC changes in a network‐specific manner in bvFTD and AD+MCI patients, which may be in turn be predictive of cognitive decline. Our study suggest that axonal protein loss has differential effects on functional brain networks in different dementia subtypes. Future studies are warranted to confirm these findings in a larger cohort.

Default mode network functional connectivity strength in utero and the association with fetal subcortical development.

The default mode network is essential for higher-order cognitive processes and is composed of an extensive network of functional and structural connections. Early in fetal life, the default mode network shows strong connectivity with other functional networks; however, the association with structural development is not well understood. In this study, resting-state functional magnetic resonance imaging and anatomical images were acquired in 30 pregnant women with singleton pregnancies. Participants completed 1 or 2 MR imaging sessions, on average 3weeks apart (43 data sets), between 28- and 39-weeks postconceptional ages. Subcortical volumes were automatically segmented. Activation time courses from resting-state functional magnetic resonance imaging were extracted from the default mode network, medial temporal lobe network, and thalamocortical network. Generalized estimating equations were used to examine the association between functional connectivity strength between default mode network-medial temporal lobe, default mode network-thalamocortical network, and subcortical volumes, respectively. Increased functional connectivity strength in the default mode network-medial temporal lobe network was associated with smaller right hippocampal, left thalamic, and right caudate nucleus volumes, but larger volumes of the left caudate. Increased functional connectivity strength in the default mode network-thalamocortical network was associated with smaller left thalamic volumes. The strong associations seen among the default mode network functional connectivity networks and regionally specific subcortical volume development indicate the emergence of short-range connectivity in the third trimester.

Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging study.

The psychopathology of patients with anorexia nervosa has been hypothesized to involve inappropriate self-referential processing, disturbed interoceptive awareness, and excessive cognitive control, including distorted self-concern, disregard of their own starvation state, and extreme weight-control behavior. We hypothesized that the resting-state brain networks, including the default mode, salience and frontal-parietal networks, might be altered in such patients, and that treatment might normalize neural functional connectivity, with improvement of inappropriate self-cognition. We measured resting-state functional magnetic resonance images from 18 patients with anorexia nervosa and 18 healthy subjects before and after integrated hospital treatment (nourishment and psychological therapy). The default mode, salience, and frontal-parietal networks were examined using independent component analysis. Body mass index and psychometric measurements significantly improved after treatment. Before treatment, default mode network functional connectivity in the retrosplenial cortex and salience network functional connectivity in the ventral anterior insula and rostral anterior cingulate cortex were decreased in anorexia nervosa patients compared with those in controls. Interpersonal distrust was negatively correlated with salience network functional connectivity in the rostral anterior cingulate cortex. Default mode network functional connectivity in the posterior insula and frontal-parietal network functional connectivity in the angular gyrus were increased in anorexia nervosa patients compared with those in controls. Comparison between pre- and post-treatment images from patients with anorexia nervosa exhibited significant increases in default mode network functional connectivity in the hippocampus and retrosplenial cortex, and salience network functional connectivity in the dorsal anterior insula following treatment. Frontal-parietal network functional connectivity in the angular cortex showed no significant changes. The findings revealed that treatment altered the functional connectivity in several parts of default mode and salience networks in patients with anorexia nervosa. These alterations of neural function might be associated with improvement of self-referential processing and coping with sensations of discomfort following treatment for anorexia nervosa.

Alternation in functional connectivity within default mode network after psychodynamic psychotherapy in borderline personality disorder

BackgroundBorderline personality disorder (BPD) is characterized by impairments in emotion regulation, impulse control, and interpersonal and social functioning along with a deficit in emotional awareness and empathy. In this study, we investigated whether functional connectivity (FC) within the default mode network (DMN) is affected by 1-year psychodynamic psychotherapy in patients with BPD.MethodsNine BPD patients filled out the demography, Interpersonal Reactive Index (IRI), Toronto Alexithymia Scale 20 (TAS 20), the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), and the Borderline Evaluation Severity over Time (BEST) questionnaire. The BPD group (9F) and the control group (9F) had a mean ± SD age of 28.2 ± 5.3 years and 30.4 ± 6.1 years, respectively. BPD subjects underwent longitudinal resting-state fMRI before psychodynamic psychotherapy and then every 4 months for a year after initiating psychotherapy. FC in DMN was characterized by calculating the nodal degree, a measure of centrality in the graph theory.ResultsThe results indicated that patients with BPD present with aberrant DMN connectivity compared to healthy controls. Over a year of psychotherapy, the patients with BPD showed both FC changes (decreasing nodal degree in the dorsal anterior cingulate cortex and increasing in other cingulate cortex regions) and behavioral improvement in their symptoms and substance use. There was also a significant positive association between the decreased nodal degree in regions of the dorsal cingulate cortex and a decrease in the score of the TAS-20 indicating difficulty in identifying feelings after psychotherapy.ConclusionIn BPD, there is altered FC within the DMN and disruption in self-processing and emotion regulation. Psychotherapy may modify the DMN connectivity and that modification is associated with positive changes in BPD emotional symptoms.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, &amp; Neuroimaging Advancing the Field of Neurology

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, &amp; Neuroimaging Advancing the Field of Neurology

Altered longitudinal trajectory of default mode network connectivity in healthy youth with subclinical depressive and posttraumatic stress symptoms

The default mode network (DMN) plays a crucial role in internal self-processing, rumination, and social functions. Disruptions to DMN connectivity have been linked with early adversity and the emergence of psychopathology in adolescence and early adulthood. Herein, we investigate how subclinical psychiatric symptoms can impact DMN functional connectivity during the pubertal transition. Resting-state fMRI data were collected annually from 190 typically-developing youth (9–15 years-old) at three timepoints and within-network DMN connectivity was computed. We used latent growth curve modeling to determine how self-reported depressive and posttraumatic stress symptoms predicted rates of change in DMN connectivity over the three-year period. In the baseline model without predictors, we found no systematic changes in DMN connectivity over time. However, significant modulation emerged after adding psychopathology predictors; greater depressive symptomatology was associated with significant decreases in connectivity over time, whereas posttraumatic stress symptoms were associated with significant increases in connectivity over time. Follow-up analyses revealed that these effects were driven by connectivity changes involving the dorsal medial prefrontal cortex subnetwork. In conclusion, these data suggest that subclinical depressive and posttraumatic symptoms alter the trajectory of DMN connectivity, which may indicate that this network is a nexus of clinical significance in mental health disorders.

Functional connectivity abnormalities of brain networks in obsessive–compulsive disorder: a systematic review

Obsessive-compulsive disorder (OCD) is characterized by cognitive abnormalities encompassing several executive processes. Neuroimaging studies highlight functional abnormalities of executive fronto-parietal network (FPN) and default-mode network (DMN) in OCD patients, as well as of the prefrontal cortex (PFC) more specifically. We aim at assessing the presence of functional connectivity (FC) abnormalities of intrinsic brain networks and PFC in OCD, possibly underlying specific computational impairments and clinical manifestations. A systematic review of resting-state fMRI studies investigating FC was conducted in unmedicated OCD patients by querying three scientific databases (PubMed, Scopus, PsycInfo) up to July 2022 (search terms: “obsessive–compulsive disorder” AND “resting state” AND “fMRI” AND “function* *connect*” AND “task-positive” OR “executive” OR “central executive” OR “executive control” OR “executive-control” OR “cognitive control” OR “attenti*” OR “dorsal attention” OR “ventral attention” OR “frontoparietal” OR “fronto-parietal” OR “default mode” AND “network*” OR “system*”). Collectively, 20 studies were included. A predominantly reduced FC of DMN – often related to increased symptom severity – emerged. Additionally, intra-network FC of FPN was predominantly increased and often positively related to clinical scores. Concerning PFC, a predominant hyper-connectivity of right-sided prefrontal links emerged. Finally, FC of lateral prefrontal areas correlated with specific symptom dimensions. Several sources of heterogeneity in methodology might have affected results in unpredictable ways and were discussed. Such findings might represent endophenotypes of OCD manifestations, possibly reflecting computational impairments and difficulties in engaging in self-referential processes or in disengaging from cognitive control and monitoring processes.

Associations between Elemental Metabolic Dynamics and Default Mode Network Functional Connectivity Are Altered in Autism.

Autism is a neurodevelopmental condition associated with atypical social communication, cognitive, and sensory faculties. Recent advances in exposure biology suggest that biomarkers of elemental uptake and metabolism measured in hair samples can yield an effective signal predictive of autism diagnosis. Here, we investigated if elemental biomarkers in hair were associated with functional connectivity in regions of the default mode network (DMN) previously linked to autism. In a study sample which included twin pairs with concordant and discordant diagnoses for autism, our analysis of hair samples and neuroimaging data supported two general findings. First, independent of autism diagnosis, we found a broad pattern of association between elemental biomarkers and functional connectivity in the DMN, which primarily involved dynamics in zinc metabolism. Second, we found that associations between the DMN and elemental biomarkers, particularly involving phosphorus, calcium, manganese, and magnesium, differed significantly in autistic participants from control participants. In sum, these findings suggest that functional dynamics in elemental metabolism relate broadly to persistent patterns of functional connectivity in the DMN, and that these associations are altered in the emergence of autism.

Brief diesel exhaust exposure acutely impairs functional brain connectivity in humans: a randomized controlled crossover study

BackgroundWhile it is known that exposure to traffic-related air pollution causes an enormous global toll on human health, neurobiological underpinnings therein remain elusive. The study addresses this gap in knowledge.MethodsWe performed the first controlled human exposure study using functional MRI with an efficient order-randomized double-blind crossover study of diesel exhaust (DE) and control (filtered air; FA) in 25 healthy adults (14 males, 11 females; 19–49 years old; no withdrawals). Analyses were carried out using a mixed effects model in FLAME. Z (Gaussianised T/F) statistic images were thresholded non-parametrically using clusters determined by Z > 2.3 and a (corrected) cluster significance threshold of p = 0.05.ResultsAll 25 adults went through the exposures and functional MRI imaging were collected. Exposure to DE yielded a decrease in functional connectivity compared to exposure to FA, shown through the comparison of DE and FA in post-exposure measurement of functional connectivity.ConclusionWe observed short-term pollution-attributable decrements in default mode network functional connectivity. Decrements in brain connectivity causes many detrimental effects to the human body so this finding should guide policy change in air pollution exposure regulation.Trial registrationUniversity of British Columbia Clinical Research Ethics Board (# H12-03025), Vancouver Coastal Health Ethics Board (# V12-03025), and Health Canada’s Research Ethics Board (# 2012-0040).

Decreased default mode network functional connectivity with visual processing regions as potential biomarkers for delayed neurocognitive recovery: A resting-state fMRI study and machine-learning analysis.

The abnormal functional connectivity (FC) pattern of default mode network (DMN) may be key markers for early identification of various cognitive disorders. However, the whole-brain FC changes of DMN in delayed neurocognitive recovery (DNR) are still unclear. Our study was aimed at exploring the whole-brain FC patterns of all regions in DMN and the potential features as biomarkers for the prediction of DNR using machine-learning algorithms. Resting-state functional magnetic resonance imaging (fMRI) was conducted before surgery on 74 patients undergoing non-cardiac surgery. Seed-based whole-brain FC with 18 core regions located in the DMN was performed, and FC features that were statistically different between the DNR and non-DNR patients after false discovery correction were extracted. Afterward, based on the extracted FC features, machine-learning algorithms such as support vector machine, logistic regression, decision tree, and random forest were established to recognize DNR. The machine learning experiment procedure mainly included three following steps: feature standardization, parameter adjustment, and performance comparison. Finally, independent testing was conducted to validate the established prediction model. The algorithm performance was evaluated by a permutation test. We found significantly decreased DMN connectivity with the brain regions involved in visual processing in DNR patients than in non-DNR patients. The best result was obtained from the random forest algorithm based on the 20 decision trees (estimators). The random forest model achieved the accuracy, sensitivity, and specificity of 84.0, 63.1, and 89.5%, respectively. The area under the receiver operating characteristic curve of the classifier reached 86.4%. The feature that contributed the most to the random forest model was the FC between the left retrosplenial cortex/posterior cingulate cortex and left precuneus. The decreased FC of DMN with regions involved in visual processing might be effective markers for the prediction of DNR and could provide new insights into the neural mechanisms of DNR. : Chinese Clinical Trial Registry, ChiCTR-DCD-15006096.

Functional disconnection between subsystems of the default mode network in bipolar disorder

BackgroundDisruption in connectivity between default mode network (DMN) regions has previously been reported in bipolar disorder (BD). The current study aimed to investigate the dysfunction of the DMN subsystem in patients with BD during manic and depressive episodes and to explore its relationship with the symptoms of BD. MethodsFifty-two patients with bipolar disorder and 39 healthy controls were recruited. Eleven seed points were selected from three DMN subsystems. We performed seed-based resting-state functional connectivity (FC) analysis and obtained individual DMN FC matrices by computing the spatial correlations between pairs of FC maps. The strength of the connections within and between the three DMN subsystems, including the core subsystem, dorsal medial prefrontal cortex subsystem, and medial temporal lobe (MTL) subsystem, was used for group analyses. ResultsCompared with healthy controls, reduced FC between the core and MTL subsystem was observed in BD patients, especially in those with depressive episodes, but not in those with manic episodes. There were significant differences in core-MTL connectivity strength between the two patient groups during manic and depressive episodes. Moreover, core-MTL subsystem connectivity was negatively correlated with the depression scale. The FC within the core subsystem was negatively correlated with anxiety and negatively correlated with depression. ConclusionThis study provides evidence for an abnormal default network subsystem connection in bipolar disorder during manic and depressive episodes, revealing the neuropathological mechanism of the disease from the perspective of brain functional connectivity.

Sex differences in effects of tDCS and language treatments on brain functional connectivity in primary progressive aphasia

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language functions. Neuromodulatory techniques (e.g., transcranial direct current stimulation, active-tDCS) and behavioral (speech-language) therapy have shown promising results in treating speech and language deficits in PPA patients. One mechanism of active-tDCS efficacy is through modulation of network functional connectivity (FC). It remains unknown how biological sex influences FC and active-tDCS or language treatment(s). In the current study, we compared sex differences, induced by active-tDCS and language therapy alone, in the default mode and language networks, acquired during resting-state fMRI in 36 PPA patients. Using a novel statistical method, the covariate-assisted-principal-regression (CAPs) technique, we found sex and age differences in FC changes following active-tDCS. In the default mode network (DMN): (1) men (in both conditions) showed greater FC in DMN than women. (2) men who received active-tDCS showed greater FC in the DMN than men who received language-treatment only. In the language network: (1) women who received active-tDCS showed significantly greater FC across the language network than women who received sham-tDCS. As age increases, regardless of sex and treatment condition, FC in language regions decreases. The current findings suggest active-tDCS treatment in PPA alters network-specific FC in a sex-dependent manner.

State of Brain Networks in Long Covid: Post Mild to Moderate Acute Covid -19 Disease

Background: Long Covid is a well-known entity in patients who recovered from acute Covid-19 disease and this phase is dominated by neurological complaints chiefly fatigue, palpitations and sleep disorders. This study was designed to assess the functional connectivity of the major brain networks in patients who recovered from mild to moderate Covid-19 disease. Methods: A observational study comprising of 100 consecutive symptomatic patients without any prior neurological disorder was conducted using resting state (rs) functional MRI. Post processing was done for both in-network and between-network connectivity of eight major brain networks and results statistically analyzed and correlated with clinical symptoms. Results: 91% patients presented with fatigue and showed marked reduced activity of medial frontal cortex (MFC) of the default mode network (DMN) with reduced functional connectivity (FC) of DMN with Salience (SALIEN) network, Sensorimotor network (SMN), Dorsal attention network (DAN) with compensatory overactivity of right lateral posterior parietal node (LPP) which was a characteristic feature. PTSD was second commonest with 80% patients showing reduced FC of DMN, SALIEN, Language network (LANGN) with overactivity of Visual network (VISN) and the cerebellum. 77% patients had anosognosia and showing characteristic overactivity of basal ganglia network (BGN) with reduced FC of DMN, SALIEN, SMN. Conclusion: Long covid patients show major altered FC of both in and between networks with DMN being most commonly affected with severely reduced FC of MFC. Fatigue patients showed a characteristic signature of overactive right LPP. PTSD patients had increased VISN and cerebellar BOLD activity while in anosgnosia a characteristic BGN over activity was seen.

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

A Combined Intervention of Aerobic Exercise and Video Game in Older Adults: The Efficacy and Neural Basis on Improving Mnemonic Discrimination.

Mnemonic discrimination is very vulnerable to aging. Previous studies have reported that aerobic exercise and enriched cognitive stimulation (e.g., video games) could improve mnemonic discrimination in older adults. The animal model suggested that combining the 2 training methods could result in a larger improvement. However, there is limited evidence on the potential superior efficacy of combined intervention with human participants. Moreover, the neural basis of this potential superior is poorly understood. We conducted a 16-week intervention trial with 98 community-dwelling older adults assigned to one of the four groups (combined training, aerobic cycling alone, video game alone, or passive control). Mnemonic discrimination was measured as the primary behavioral outcome, hippocampal volume, and functional connectivity of the default mode network (DMN) were measured as neural indicators. Participants receiving the combined intervention demonstrated the largest effect size of mnemonic discrimination improvement. Magnetic resonance image results indicated aerobic exercising increased left hippocampal volume, while video-game training counteracted the decline of DMN functional connectivity with aging. The synergy of hippocampal structural and functional plasticity observed in the combined training group explained why the largest intervention benefits were obtained by this group. Despite the nonrandomized design (i.e., likely self-selection bias), our results provide new evidence that combined intervention of exercise and cognitive training is more effective than single intervention for older adults. Parallel to animal studies, aerobic exercise and the video game with enriched cognitive stimulation could induce hippocampal plasticity through separate structural and functional pathways. ChiCTR1900022702.

Plasma NfL predicts default mode network functional connectivity in older adults at higher risk for Alzheimer’s disease

AbstractBackgroundNeurofilament 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.