Frequency‐specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity

Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal‐cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network‐targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta‐burst stimulation, intermittent theta‐burst stimulation, and beta‐frequency (20‐Hz) repetitive stimulation, and one sham condition. Resting‐state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta‐burst stimulation conditions would most strongly influence hippocampal‐HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta‐band activity for HCN memory function. Continuous theta‐burst stimulation improved item retrieval success relative to sham and relative to beta‐frequency stimulation, whereas intermittent theta‐burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta‐burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory‐related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta‐burst stimulation affected memory‐related hippocampal‐HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory‐related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta‐burst noninvasive stimulation.     

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto‐temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto‐temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1‐week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto‐temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1‐week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto‐temporal dysconnectivity. Patterns of fronto‐temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442–1457, 2015. © 2014 Wiley Periodicals, Inc.     

Abnormal distraction and load‐specific connectivity during working memory in cognitively normal Parkinson's disease

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context‐dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load‐modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context‐related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context‐dependent connectivity. During encoding, striatal‐prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long‐range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context‐specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory‐related signatures of aberrant cortico–cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.     

Frequency‐specific age‐related decreased brain network diversity in cognitively healthy elderly: A whole‐brain data‐driven analysis

Age‐related changes in functional brain network have been well documented. However, recent studies have suggested the nonstationary properties of the functional connectivity of the brain, and little is known about the changes of functional connectivity dynamics during aging. In this study, a two‐step singular value decomposition was introduced to capture the dynamic patterns of the time‐varying functional connectivity in different frequency intervals, and the whole‐brain and regional brain diversity were quantified by using Shannon entropy. The relationships between age and functional connectivity dynamics were investigated in a relatively large sample cohort of cognitively healthy elderly (N = 188, ages 65–80). The results showed an age‐related decreased diversity in the whole brain as well as in the right inferior frontal gyrus, right amygdala, right hippocampus, left parahippocampal, and left inferior parietal gyrus in the frequency interval of 0.06–0.12 Hz. In addition, the whole‐brain diversity during resting state could also reflect the general mental flexibility. This study provided the first evidence of frequency‐specific age effects on the functional connectivity dynamics in cognitively healthy elderly, and may shed new light on the dynamic functional connectivity analysis of aging and neurodegenerative diseases.     

Hippocampal functional connectivity and episodic memory in early childhood

Episodic memory relies on a distributed network of brain regions, with the hippocampus playing a critical and irreplaceable role. Few studies have examined how changes in this network contribute to episodic memory development early in life. The present addressed this gap by examining relations between hippocampal functional connectivity and episodic memory in 4- and 6-year-old children (n = 40). Results revealed similar hippocampal functional connectivity between age groups, which included lateral temporal regions, precuneus, and multiple parietal and prefrontal regions, and functional specialization along the longitudinal axis. Despite these similarities, developmental differences were also observed. Specifically, 3 (of 4) regions within the hippocampal memory network were positively associated with episodic memory in 6-year-old children, but negatively associated with episodic memory in 4-year-old children. In contrast, all 3 regions outside the hippocampal memory network were negatively associated with episodic memory in older children, but positively associated with episodic memory in younger children. These interactions are interpreted within an interactive specialization framework and suggest the hippocampus becomes functionally integrated with cortical regions that are part of the hippocampal memory network in adults and functionally segregated from regions unrelated to memory in adults, both of which are associated with age-related improvements in episodic memory ability.     

Intrinsic functional connectivity variance and state‐specific under‐connectivity in autism

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered brain connectivity. Previous neuroimaging research demonstrates inconsistent results, particularly in studies of functional connectivity in ASD. Typically, these inconsistent findings are results of studies using static measures of resting‐state functional connectivity. Recent work has demonstrated that functional brain connections are dynamic, suggesting that static connectivity metrics fail to capture nuanced time‐varying properties of functional connections in the brain. Here we used a dynamic functional connectivity approach to examine the differences in the strength and variance of dynamic functional connections between individuals with ASD and healthy controls (HCs). The variance of dynamic functional connections was defined as the respective standard deviations of the dynamic functional connectivity strength across time. We utilized a large multicenter dataset of 507 male subjects (209 with ASD and 298 HC, from 6 to 36 years old) from the Autism Brain Imaging Data Exchange (ABIDE) to identify six distinct whole‐brain dynamic functional connectivity states. Analyses demonstrated greater variance of widespread long‐range dynamic functional connections in ASD (P < 0.05, NBS method) and weaker dynamic functional connections in ASD (P < 0.05, NBS method) within specific whole‐brain connectivity states. Hypervariant dynamic connections were also characterized by weaker connectivity strength in ASD compared with HC. Increased variance of dynamic functional connections was also related to ASD symptom severity (ADOS total score) (P < 0.05), and was most prominent in connections related to the medial superior frontal gyrus and temporal pole. These results demonstrate that greater intraindividual dynamic variance is a potential biomarker of ASD. Hum Brain Mapp 38:5740–5755, 2017. © 2017 Wiley Periodicals, Inc.     

A combined diffusion‐weighted and electroencephalography study on age‐related differences in connectivity in the motor network during bimanual performance

We studied the relationship between age‐related differences in inter‐ and intra‐hemispheric structural and functional connectivity in the bilateral motor network. Our focus was on the correlation between connectivity and declined motor performance in older adults. Structural and functional connectivity were estimated using diffusion weighted imaging and resting‐state electro‐encephalography, respectively. A total of 48 young and older healthy participants were measured. In addition, motor performances were assessed using bimanual coordination tasks. To pre‐select regions‐of‐interest (ROIs), a neural model was adopted that accounts for intra‐hemispheric functional connectivity between dorsal premotor area (PMd) and primary motor cortex (M1) and inter‐hemispheric connections between left and right M1 (M1_L and M1_R). Functional connectivity was determined via the weighted phase‐lag index (wPLI) in the source‐reconstructed beta activity during rest. We quantified structural connectivity using kurtosis anisotropy (KA) values of tracts derived from diffusion tensor‐based fiber tractography between the aforementioned areas. In the group of older adults, wPLI values between M1_L–M1_R were negatively associated with the quality of bimanual motor performance. The additional association between wPLI values of PMd_L––M1_L and PMd_R–M1_L supports that functional connectivity with the left hemisphere mediated (bimanual) motor control in older adults. The correlational analysis between the selected structural and functional connections revealed a strong association between wPLI values in the left intra‐hemispheric PMd_L–M1_L pathway and KA values in M1_L–M1_R and PMd_R–M1_L pathways in the group of older adults. This suggests that weaker structural connections in older adults correlate with stronger functional connectivity and, hence, poorer motor performance.     

Hippocampal‐striatal functional connectivity supports processing of temporal expectations from associative memory

The hippocampus and dorsal striatum are both associated with temporal processing, but they are thought to play distinct roles. The hippocampus has been reported to contribute to storing temporal structure of events in memory, whereas the striatum contributes to temporal motor preparation and reward anticipation. Here, we asked whether the striatum cooperates with the hippocampus in processing the temporal context of memorized visual associations. In our task, participants were trained to implicitly form temporal expectations for one of two possible time intervals associated to specific cue‐target associations, and subsequently were scanned using ultra‐high‐field 7T functional magnetic resonance imaging. During scanning, learned temporal expectations could be violated when the pairs were presented at either the associated or not‐associated time intervals. When temporal expectations were met during testing trials, activity in left and right hippocampal subfields and right putamen decreased, compared to when temporal expectations were not met. Further, psycho‐physiological interactions showed that functional connectivity between left hippocampal subfields and caudate decreased when temporal expectations were not met. Our results indicate that the hippocampus and striatum cooperate to process implicit temporal expectation from mnemonic associations. Our findings provide further support for a hippocampal‐striatal network in temporal associative processing.     

Baseline frontostriatal‐limbic connectivity predicts reward‐based memory formation

Reward mediates the acquisition and long‐term retention of procedural skills in humans. Yet, learning under rewarded conditions is highly variable across individuals and the mechanisms that determine interindividual variability in rewarded learning are not known. We postulated that baseline functional connectivity in a large‐scale frontostriatal‐limbic network could predict subsequent interindividual variability in rewarded learning. Resting‐state functional MRI was acquired in two groups of subjects (n = 30) who then trained on a visuomotor procedural learning task with or without reward feedback. We then tested whether baseline functional connectivity within the frontostriatal‐limbic network predicted memory strength measured immediately, 24 h and 1 month after training in both groups. We found that connectivity in the frontostriatal‐limbic network predicted interindividual variability in the rewarded but not in the unrewarded learning group. Prediction was strongest for long‐term memory. Similar links between connectivity and reward‐based memory were absent in two control networks, a fronto‐parieto‐temporal language network and the dorsal attention network. The results indicate that baseline functional connectivity within the frontostriatal‐limbic network successfully predicts long‐term retention of rewarded learning. Hum Brain Mapp 35:5921–5931, 2014. © 2014 Wiley Periodicals, Inc.     

Interrelating differences in structural and functional connectivity in the older adult's brain

In the normal aging process, the functional connectome restructures and shows a shift from more segregated to more integrated brain networks, which manifests itself in highly different cognitive performances in older adults. Underpinnings of this reorganization are not fully understood, but may be related to age‐related differences in structural connectivity, the underlying scaffold for information exchange between regions. The structure–function relationship might be a promising factor to understand the neurobiological sources of interindividual cognitive variability, but remain unclear in older adults. Here, we used diffusion weighted and resting‐state functional magnetic resonance imaging as well as cognitive performance data of 573 older subjects from the 1000BRAINS cohort (55–85 years, 287 males) and performed a partial least square regression on 400 regional functional and structural connectivity (FC and SC, respectively) estimates comprising seven resting‐state networks. Our aim was to identify FC and SC patterns that are, together with cognitive performance, characteristic of the older adults aging process. Results revealed three different aging profiles prevalent in older adults. FC was found to behave differently depending on the severity of age‐related SC deteriorations. A functionally highly interconnected system is associated with a structural connectome that shows only minor age‐related decreases. Because this connectivity profile was associated with the most severe age‐related cognitive decline, a more interconnected FC system in older adults points to a process of dedifferentiation. Thus, functional network integration appears to increase primarily when SC begins to decline, but this does not appear to mitigate the decline in cognitive performance.     

Flexible connectivity in the aging brain revealed by task modulations

Recent studies have shown that aging has a large impact on connectivity within and between functional networks. An open question is whether elderly still have the flexibility to adapt functional network connectivity (FNC) to the demands of the task at hand. To study this, we collected fMRI data in younger and older participants during resting state, a selective attention (SA) task and an n‐back working memory task with varying levels of difficulty. Spatial independent component (IC) analysis was used to identify functional networks over all participants and all conditions. Dual regression was used to obtain participant and task specific time‐courses per IC. Subsequently, functional connectivity was computed between all ICs in each of the tasks. Based on these functional connectivity matrices, a scaled version of the eigenvector centrality (SEC) was used to measure the total influence of each IC in the complete graph of ICs. The results demonstrated that elderly remain able to adapt FNC to task demands. However, there was an age‐related shift in the impetus for FNC change. Older participants showed the maximal change in SEC patterns between resting state and the SA task. Young participants, showed the largest shift in SEC patterns between the less demanding SA task and the more demanding 2‐back task. Our results suggest that increased FNC changes from resting state to low demanding tasks in elderly reflect recruitment of additional resources, compared with young adults. The lack of change between the low and high demanding tasks suggests that elderly reach a resource ceiling. Hum Brain Mapp 35:3788–3804, 2014. © 2013 Wiley Periodicals, Inc.     

The relationship between level of processing and hippocampal–cortical functional connectivity during episodic memory formation in humans

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing‐independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal–cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long‐term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Reduced specificity of functional connectivity in the aging brain during task performance

The importance of studying connectivity in the aging brain is increasingly recognized. Recent studies have shown that connectivity within the default mode network is reduced with age and have demonstrated a clear relation of these changes with cognitive functioning. However, research on age‐related changes in other functional networks is sparse and mainly focused on prespecified functional networks. Using functional magnetic resonance imaging, we investigated age‐related changes in functional connectivity during a visual oddball task in a range of functional networks. It was found that compared with young participants, elderly showed a decrease in connectivity between areas belonging to the same functional network. This was found in the default mode network and the somatomotor network. Moreover, in all identified networks, elderly showed increased connectivity between areas within these networks and areas belonging to different functional networks. Decreased connectivity within functional networks was related to poorer cognitive functioning in elderly. The results were interpreted as a decrease in the specificity of functional networks in older participants. Hum Brain Mapp 35:319–330, 2014. © 2012 Wiley Periodicals, Inc.     

Working memory‐related changes in functional connectivity persist beyond task disengagement

We examined whether altered connectivity in functional networks during working memory performance persists following conclusion of that performance, into a subsequent resting state. We conducted functional magnetic resonance imaging (fMRI) in 50 young adults during an initial resting state, followed by an N‐back working memory task and a subsequent resting state, in order to examine changes in functional connectivity within and between the default‐mode network (DMN) and the task‐positive network (TPN) across the three states. We found that alterations in connectivity observed during the N‐back task persisted into the subsequent resting state within the TPN and between the DMN and TPN, but not within the DMN. Further, both speed of working memory performance and TPN connectivity strength during the N‐back task predicted connectivity strength in the subsequent resting state. Finally, DMN connectivity measured before and during the N‐back task predicted individual differences in self‐reported inattentiveness, but this association was not found during the post‐task resting state. Together, these findings have important implications for models of how the brain recovers following effortful cognition, as well as for experimental designs using resting and task scans. Hum Brain Mapp 35:1004–1017, 2014. © 2012 Wiley Periodicals, Inc.     

Structural and functional connectivity in healthy aging: Associations for cognition and motor behavior

Age‐related behavioral declines may be the result of deterioration of white matter tracts, affecting brain structural (SC) and functional connectivity (FC) during resting state. To date, it is not clear if the combination of SC and FC data could better predict cognitive/motor performance than each measure separately. We probed these relationships in the cingulum bundle, a major white matter pathway of the default mode network. We aimed to attain deeper knowledge about: (a) the relationship between age and the cingulum's SC and FC strength, (b) the association between SC and FC, and particularly (c) how the cingulum's SC and FC are related to cognitive/motor performance separately and combined. We examined these associations in a healthy and well‐educated sample of 165 older participants (aged 64‐85). SC and FC were acquired using probabilistic tractography to derive measures to capture white matter integrity within the cingulum bundle (fractional anisotropy, mean, axial and radial diffusivity) and a seed‐based resting‐state functional MRI correlation approach, respectively. Participants performed cognitive tests measuring processing speed, memory and executive functions, and motor tests measuring motor speed and grip force. Our data revealed that only SC but not resting state FC was significantly associated with age. Further, the cingulum's SC and FC showed no relation. Different relationships between cognitive/motor performance and SC/FC separately were found, but no additive effect of the combined analysis of cingulum's SC and FC for predicting cognitive/motor performance was apparent. Hum Brain Mapp 37:855–867, 2016. © 2015 Wiley Periodicals, Inc .     

Age‐related alterations in functional connectivity along the longitudinal axis of the hippocampus and its subfields

Hippocampal circuit alterations that differentially affect hippocampal subfields are associated with age‐related memory decline. Additionally, functional organization along the longitudinal axis of the hippocampus has revealed distinctions between anterior and posterior (A‐P) connectivity. Here, we examined the functional connectivity (FC) differences between young and older adults at high‐resolution within the medial temporal lobe network (entorhinal, perirhinal, and parahippocampal cortices), allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. Overall, we found reliably greater connectivity for younger adults than older adults between the hippocampus and parahippocampal cortex (PHC) and perirhinal cortex (PRC). This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra‐hippocampal connectivity also reflected an age‐related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. Interestingly, the anterior–posterior dysfunction in older adults between hippocampus and PHC was predictive of lure discrimination performance on the Mnemonic similarity task (MST), suggesting a role in memory performance. While age‐related dysfunction within the hippocampal subfields has been well‐documented, these results suggest that the age‐related dysfunction in hippocampal connectivity across the longitudinal axis may also contribute significantly to memory decline in older adults.     

Dynamic connectivity among cortical layers in local and large‐scale sensory processing

Cortical processing of sensory stimuli typically recruits multiple areas, but how each area dynamically incorporates activity from other areas is not well understood. We investigated interactions between cortical columns of bilateral primary sensory regions (S1s) in rats by recording local field potentials and multi‐unit activity simultaneously in both S1s with electrodes positioned at each cortical layer. Using dynamic connectivity analysis based on Granger‐causal modeling, we found that, shortly after whisker stimulation (< 10 ms), contralateral S1 (cS1) already relays activity to granular and infragranular layers of S1 in the other hemisphere, after which cS1 shows a pattern of within‐column interactions that directs activity upwards toward superficial layers. This pattern of predominant upward driving was also observed in S1 ipsilateral to stimulation, but at longer latencies. In addition, we found that interactions between the two S1s most strongly target granular and infragranular layers. Taken together, the results suggest a possible mechanism for how cortical columns integrate local and large‐scale neocortical computation by relaying information from deeper layers to local processing in superficial layers.     

Predicting episodic and spatial memory performance from hippocampal resting‐state functional connectivity: Evidence for an anterior–posterior division of function

fMRI studies have identified distinct resting‐state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task‐related fMRI point to a role for the anterior hippocampus in nonspatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine‐learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole‐brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole‐brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting‐state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.     

Recognition memory is associated with altered resting‐state functional connectivity in people at genetic risk for Alzheimer's disease

The apolipoprotein E ε4 (ApoE ε4) allele not only represents the strongest single genetic risk factor for sporadic Alzheimer's disease, but also imposes independent effects on brain function in healthy individuals where it has been shown to promote subtle memory deficits and altered intrinsic functional brain network connectivity. Based on previous work showing a potential relevance of the default mode network (DMN) functional connectivity for episodic memory function, we hypothesized that the ApoE ε4 genotype would affect memory performance via modulation of the DMN. We assessed 63 healthy individuals (50–80 years old), of which 20 carried the ε4 allele. All participants underwent resting‐state functional magnetic resonance imaging (fMRI), high‐resolution 3D anatomical MRI imaging and neuropsychological assessment. Functional connectivity analysis of resting‐state activity was performed with a predefined seed region located in the left posterior cingulate cortex (PCC), a core region of the DMN. ApoE ε4 carriers performed significantly poorer than non‐carriers in wordlist recognition and cued recall. Furthermore, ε4 carriers showed increased connectivity relative to ε4 non‐carriers between the PCC seed region and left‐hemispheric middle temporal gyrus (MTG). There was a positive correlation between recognition memory scores and resting‐state connectivity in the left MTG in ε4 carriers. These results can be interpreted as compensatory mechanisms strengthening the cross‐links between DMN core areas and cortical areas involved in memory processing.