Hippocampal Functions Modulate Transfer-Appropriate Cortical Representations Supporting Subsequent Memory.

The hippocampus plays a central role as a coordinate system or index of information stored in neocortical loci. Nonetheless, it remains unclear how hippocampal processes integrate with cortical information to facilitate successful memory encoding. Thus, the goal of the current study was to identify specific hippocampal-cortical interactions that support object encoding. We collected fMRI data while 19 human participants (7 female and 12 male) encoded images of real-world objects and tested their memory for object concepts and image exemplars (i.e., conceptual and perceptual memory). Representational similarity analysis revealed robust representations of visual and semantic information in canonical visual (e.g., occipital cortex) and semantic (e.g., angular gyrus) regions in the cortex, but not in the hippocampus. Critically, hippocampal functions modulated the mnemonic impact of cortical representations that are most pertinent to future memory demands, or transfer-appropriate representations Subsequent perceptual memory was best predicted by the strength of visual representations in ventromedial occipital cortex in coordination with hippocampal activity and pattern information during encoding. In parallel, subsequent conceptual memory was best predicted by the strength of semantic representations in left inferior frontal gyrus and angular gyrus in coordination with either hippocampal activity or semantic representational strength during encoding. We found no evidence for transfer-incongruent hippocampal-cortical interactions supporting subsequent memory (i.e., no hippocampal interactions with cortical visual/semantic representations supported conceptual/perceptual memory). Collectively, these results suggest that diverse hippocampal functions flexibly modulate cortical representations of object properties to satisfy distinct future memory demands.Significance Statement The hippocampus is theorized to index pieces of information stored throughout the cortex to support episodic memory. Yet how hippocampal processes integrate with cortical representation of stimulus information remains unclear. Using fMRI, we examined various forms of hippocampal-cortical interactions during object encoding in relation to subsequent performance on conceptual and perceptual memory tests. Our results revealed novel hippocampal-cortical interactions that utilize semantic and visual representations in transfer-appropriate manners: conceptual memory supported by hippocampal modulation of frontoparietal semantic representations, and perceptual memory supported by hippocampal modulation of occipital visual representations. These findings provide important insights into the neural mechanisms underlying the formation of information-rich episodic memory and underscore the value of studying the flexible interplay between brain regions for complex cognition.

Visual Recognition Memory of Scenes Is Driven by Categorical, Not Sensory, Visual Representations.

When we perceive a scene, our brain processes various types of visual information simultaneously, ranging from sensory features, such as line orientations and colors, to categorical features, such as objects and their arrangements. Whereas the role of sensory and categorical visual representations in predicting subsequent memory has been studied using isolated objects, their impact on memory for complex scenes remains largely unknown. To address this gap, we conducted an fMRI study in which female and male participants encoded pictures of familiar scenes (e.g., an airport picture) and later recalled them, while rating the vividness of their visual recall. Outside the scanner, participants had to distinguish each seen scene from three similar lures (e.g., three airport pictures). We modeled the sensory and categorical visual features of multiple scenes using both early and late layers of a deep convolutional neural network. Then, we applied representational similarity analysis to determine which brain regions represented stimuli in accordance with the sensory and categorical models. We found that categorical, but not sensory, representations predicted subsequent memory. In line with the previous result, only for the categorical model, the average recognition performance of each scene exhibited a positive correlation with the average visual dissimilarity between the item in question and its respective lures. These results strongly suggest that even in memory tests that ostensibly rely solely on visual cues (such as forced-choice visual recognition with similar distractors), memory decisions for scenes may be primarily influenced by categorical rather than sensory representations.

Using diffusion tensor imaging to effectively target TMS to deep brain structures.

TMS has become a powerful tool to explore cortical function, and in parallel has proven promising in the development of therapies for various psychiatric and neurological disorders. Unfortunately, much of the inference of the direct effects of TMS has been assumed to be limited to the area a few centimeters beneath the scalp, though clearly more distant regions are likely to be influenced by structurally connected stimulation sites. In this study, we sought to develop a novel paradigm to individualize TMS coil placement to non-invasively achieve activation of specific deep brain targets of relevance to the treatment of psychiatric disorders. In ten subjects, structural diffusion imaging tractography data were used to identify an accessible cortical target in the right frontal pole that demonstrated both anatomic and functional connectivity to right Brodmann area 25 (BA25). Concurrent TMS-fMRI interleaving was used with a series of single, interleaved TMS pulses applied to the right frontal pole at four intensity levels ranging from 80% to 140% of motor threshold. In nine of ten subjects, TMS to the individualized frontal pole sites resulted in significant linear increase in BOLD activation of BA25 with increasing TMS intensity. The reliable activation of BA25 in a dosage-dependent manner suggests the possibility that the careful combination of imaging with TMS can make use of network properties to help overcome depth limitations and allow noninvasive brain stimulation to influence deep brain structures.

Visual and Semantic Representations Predict Subsequent Memory in Perceptual and Conceptual Memory Tests.

It is generally assumed that the encoding of a single event generates multiple memory representations, which contribute differently to subsequent episodic memory. We used functional magnetic resonance imaging (fMRI) and representational similarity analysis to examine how visual and semantic representations predicted subsequent memory for single item encoding (e.g., seeing an orange). Three levels of visual representations corresponding to early, middle, and late visual processing stages were based on a deep neural network. Three levels of semantic representations were based on normative observed ("is round"), taxonomic ("is a fruit"), and encyclopedic features ("is sweet"). We identified brain regions where each representation type predicted later perceptual memory, conceptual memory, or both (general memory). Participants encoded objects during fMRI, and then completed both a word-based conceptual and picture-based perceptual memory test. Visual representations predicted subsequent perceptual memory in visual cortices, but also facilitated conceptual and general memory in more anterior regions. Semantic representations, in turn, predicted perceptual memory in visual cortex, conceptual memory in the perirhinal and inferior prefrontal cortex, and general memory in the angular gyrus. These results suggest that the contribution of visual and semantic representations to subsequent memory effects depends on a complex interaction between representation, test type, and storage location.

Age-Related Compensatory Reconfiguration of PFC Connections during Episodic Memory Retrieval.

During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related increase in PFC activity is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs versus YAs. To investigate this, we examined the age-related difference on the functional brain networks mediating episodic memory retrieval. YAs and OAs participants encoded and recalled visual scenes, and age-related differences in network topology during memory retrieval were investigated as a function of memory performance. We measured both changes in functional integration and reconfiguration in connectivity patterns. The study yielded three main findings. First, PFC regions were more functionally integrated with the rest of the brain network in OAs. Critically, this age-related increase in PFC integration was associated with better retrieval performance. Second, PFC regions showed stronger performance-related reconfiguration of connectivity patterns in OAs. Finally, the PFC reconfiguration increases in OAs tracked reconfiguration reductions in the medial temporal lobe (MTL)-a core episodic memory region, suggesting that PFC connectivity in OAs may be compensating for MTL deficits.

Cortical Overlap and Cortical-Hippocampal Interactions Predict Subsequent True and False Memory.

The declarative memory system allows us to accurately recognize a countless number of items and events, particularly those strengthened by repeated exposure. However, increased familiarity due to repetition can also lead to false recognition of related but new items, particularly when mechanisms supporting fine-grain mnemonic discrimination fail. The hippocampus is thought to be particularly important in separating overlapping cortical inputs during encoding so that similar experiences can be differentiated. In the current study of male and female human subjects, we examine how neural pattern similarity between repeated exemplars of a given concept (e.g., apple) influences true and false memory for target or lure images. Consistent with past work, we found that subsequent true recognition was related to pattern similarity between concept exemplars and the entire encoding set (global encoding similarity), particularly in ventral visual stream. In addition, memory for an individual target exemplar (a specific apple) could be predicted solely by the degree of pattern overlap between the other exemplars (different apple pictures) of that concept (concept-specific encoding similarity). Critically, subsequent false memory for lures was mitigated when high concept-specific similarity in cortical areas was accompanied by differentiated hippocampal representations of the corresponding exemplars. Furthermore, both true and false memory entailed the reinstatement of concept-related information at varying levels of specificity. These results link both true and false memory to a measure of concept strength expressed in the overlap of cortical representations, and importantly, illustrate how the hippocampus serves to separate concurrent cortical overlap in the service of detailed memory.SIGNIFICANCE STATEMENT In some instances, the same processes that help promote memory for a general idea or concept can also hinder more detailed memory judgments, which may involve differentiating between closely related items. The current study shows that increased overlap in cortical representations for conceptually-related pictures is associated with increased recognition of repeated concept pictures. Whether similar lure items were falsely remembered as old further depended on the hippocampus, where the presence of more distinct representations protected against later false memory. This work suggests that the differentiability of brain patterns during perception is related to the differentiability of items in memory, but that fine-grain discrimination depends on the interaction between cortex and hippocampus.

Structural Controllability Predicts Functional Patterns and Brain Stimulation Benefits Associated with Working Memory.

The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain-behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior.SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy.

Mapping the organization and dynamics of the posterior medial network during movie watching.

Brain regions within a posterior medial network (PMN) are characterized by sensitivity to episodic tasks, and they also demonstrate strong functional connectivity as part of the default network. Despite its cohesive structure, delineating the intranetwork organization and functional diversity of the PMN is crucial for understanding its contributions to multidimensional event cognition. Here, we probed functional connectivity of the PMN during movie watching to identify its pattern of connections and subnetwork functions in a split-sample replication of 136 participants. Consistent with prior findings of default network fractionation, we identified distinct PMN subsystems: a Ventral PM subsystem (retrosplenial cortex, parahippocampal cortex, posterior angular gyrus) and a Dorsal PM subsystem (medial prefrontal cortex, hippocampus, precuneus, posterior cingulate cortex, anterior angular gyrus). Ventral and Dorsal PM subsystems were differentiated by functional connectivity with parahippocampal cortex and precuneus and integrated by retrosplenial cortex and posterior cingulate cortex, respectively. Finally, the distinction between PMN subsystems is functionally relevant: whereas both Dorsal and Ventral PM connectivity tracked the movie content, only Ventral PM connections increased in strength at event transitions and appeared sensitive to episodic memory. Overall, these findings reveal PMN functional pathways and the distinct functional roles of intranetwork subsystems during event cognition.

Human immunodeficiency virus-related decreases in corpus callosal integrity and corresponding increases in functional connectivity.

People living with human immunodeficiency virus (PLWH) often have neurocognitive impairment. However, findings on HIV-related differences in brain network function underlying these impairments are inconsistent. One principle frequently absent from these reports is that brain function is largely emergent from brain structure. PLWH commonly have degraded white matter; we hypothesized that functional communities connected by degraded white matter tracts would show abnormal functional connectivity. We measured white matter integrity in 69 PLWH and 67 controls using fractional anisotropy (FA) in 24 intracerebral white matter tracts. Then, among tracts with degraded FA, we identified gray matter regions connected to these tracts and measured their functional connectivity during rest. Finally, we identified cognitive impairment related to these structural and functional connectivity systems. We found HIV-related decreased FA in the corpus callosum body (CCb), which coordinates activity between the left and right hemispheres, and corresponding increases in functional connectivity. Finally, we found that individuals with impaired cognitive functioning have lower CCb FA and higher CCb functional connectivity. This result clarifies the functional relevance of the corpus callosum in HIV and provides a framework in which abnormal brain function can be understood in the context of abnormal brain structure, which may both contribute to cognitive impairment.

The visual and semantic features that predict object memory: Concept property norms for 1,000 object images.

Humans have a remarkable fidelity for visual long-term memory, and yet the composition of these memories is a longstanding debate in cognitive psychology. While much of the work on long-term memory has focused on processes associated with successful encoding and retrieval, more recent work on visual object recognition has developed a focus on the memorability of specific visual stimuli. Such work is engendering a view of object representation as a hierarchical movement from low-level visual representations to higher level categorical organization of conceptual representations. However, studies on object recognition often fail to account for how these high- and low-level features interact to promote distinct forms of memory. Here, we use both visual and semantic factors to investigate their relative contributions to two different forms of memory of everyday objects. We first collected normative visual and semantic feature information on 1,000 object images. We then conducted a memory study where we presented these same images during encoding (picture target) on Day 1, and then either a Lexical (lexical cue) or Visual (picture cue) memory test on Day 2. Our findings indicate that: (1) higher level visual factors (via DNNs) and semantic factors (via feature-based statistics) make independent contributions to object memory, (2) semantic information contributes to both true and false memory performance, and (3) factors that predict object memory depend on the type of memory being tested. These findings help to provide a more complete picture of what factors influence object memorability. These data are available online upon publication as a public resource.

Examining the Role of Lateral Parietal Cortex in Emotional Distancing Using TMS.

We recently proposed a neurocognitive model of distancing-an emotion regulation tactic-with a focus on the lateral parietal cortex. Although this brain area has been implicated in both cognitive control and self-projection processes during distancing, fMRI work suggests that these processes may be dissociable here. This preregistered (NCT03698591) study tested the contribution of left temporoparietal junction (TPJ) to distancing using repetitive transcranial magnetic stimulation. We hypothesized that inhibiting left TPJ would decrease the efficiency of distancing but not distraction, another regulation tactic with similar cognitive control requirements, thus implicating this region in the self-projection processes unique to distancing. Active and sham continuous theta burst stimulation (cTBS) were applied to 30 healthy adults in a single-session crossover design. Tactic efficiency was measured using online reports of valence and effort. The stimulation target was established from the group TPJ fMRI activation peak in an independent sample using the same distancing task, and anatomical MRI scans were used for individual targeting. Analyses employed both repeated-measures ANOVA and analytic procedures tailored to crossover designs. Irrespective of cTBS, distancing led to greater decreases in negative valence over time relative to distraction, and distancing effort decreased over time while distraction effort remained stable. Exploratory analyses also revealed that active cTBS made distancing more effortful, but not distraction. Thus, left TPJ seems to support self-projection processes in distancing, and these processes may be facilitated by repeated use. These findings help to clarify the role of lateral parietal cortex in distancing and inform applications of distancing and distraction.

On the Concurrent Use of Self-System Therapy and Functional Magnetic Resonance Imaging-Guided Transcranial Magnetic Stimulation as Treatment for Depression.

OBJECTIVES: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar depression, its typical effect sizes have been modest, and methodological and conceptual challenges remain regarding how to optimize its efficacy. Linking rTMS to a model of the neurocircuitry underlying depression and applying such a model to personalize the site of stimulation may improve the efficacy of rTMS. Recent developments in the psychology and neurobiology of self-regulation offer a conceptual framework for identifying mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. We applied this framework to develop a multimodal treatment for depression by pairing self-system therapy (SST) with simultaneously administered rTMS delivered to an individually targeted region of dorsolateral prefrontal cortex identified via functional magnetic resonance imaging (fMRI). METHODS: In this proof-of-concept study, we examined the acceptability, feasibility, and preliminary efficacy of combining individually fMRI-targeted rTMS with SST. Using the format of a cognitive paired associative stimulation paradigm, the treatment was administered to 5 adults with unipolar depression in an open-label trial. RESULTS: The rTMS/SST combination was well tolerated, feasible, and acceptable. Preliminary evidence of efficacy also was promising. We hypothesized that both treatment modalities were targeting the same neural circuitry through cognitive paired associative stimulation, and observed changes in task-based fMRI were consistent with our model. These neural changes were directly related to improvements in depression severity. CONCLUSIONS: The new combination treatment represents a promising exemplar for theory-based, individually targeted, multimodal intervention in mood disorders.

Robust Resilience of the Frontotemporal Syntax System to Aging.

UNLABELLED: Brain function is thought to become less specialized with age. However, this view is largely based on findings of increased activation during tasks that fail to separate task-related processes (e.g., attention, decision making) from the cognitive process under examination. Here we take a systems-level approach to separate processes specific to language comprehension from those related to general task demands and to examine age differences in functional connectivity both within and between those systems. A large population-based sample (N = 111; 22-87 years) from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) was scanned using functional MRI during two versions of an experiment: a natural listening version in which participants simply listened to spoken sentences and an explicit task version in which they rated the acceptability of the same sentences. Independent components analysis across the combined data from both versions showed that although task-free language comprehension activates only the auditory and frontotemporal (FTN) syntax networks, performing a simple task with the same sentences recruits several additional networks. Remarkably, functionality of the critical FTN is maintained across age groups, showing no difference in within-network connectivity or responsivity to syntactic processing demands despite gray matter loss and reduced connectivity to task-related networks. We found no evidence for reduced specialization or compensation with age. Overt task performance was maintained across the lifespan and performance in older, but not younger, adults related to crystallized knowledge, suggesting that decreased between-network connectivity may be compensated for by older adults' richer knowledge base. SIGNIFICANCE STATEMENT: Understanding spoken language requires the rapid integration of information at many different levels of analysis. Given the complexity and speed of this process, it is remarkably well preserved with age. Although previous work claims that this preserved functionality is due to compensatory activation of regions outside the frontotemporal language network, we use a novel systems-level approach to show that these "compensatory" activations simply reflect age differences in response to experimental task demands. Natural, task-free language comprehension solely recruits auditory and frontotemporal networks, the latter of which is similarly responsive to language-processing demands across the lifespan. These findings challenge the conventional approach to neurocognitive aging by showing that the neural underpinnings of a given cognitive function depend on how you test it.

Frequency-specific neuromodulation of local and distant connectivity in aging and episodic memory function.

A growing literature has focused on the brain's ability to augment processing in local regions by recruiting distant communities of neurons in response to neural decline or insult. In particular, both younger and older adult populations recruit bilateral prefrontal cortex (PFC) as a means of compensating for increasing neural effort to maintain successful cognitive function. However, it remains unclear how local changes in neural activity affect the recruitment of this adaptive mechanism. To address this problem, we combined graph theoretical measures from functional MRI with diffusion weighted imaging and repetitive transcranial magnetic stimulation (rTMS) to resolve a central hypothesis: how do aged brains flexibly adapt to local changes in cortical activity? Specifically, we applied neuromodulation to increase or decrease local activity in a cortical region supporting successful memory encoding (left dorsolateral PFC or DLPFC) using 5 or 1 Hz rTMS, respectively. We then assessed a region's local within-module degree, or the distributed between-module degree (BMD) between distant cortical communities. We predicted that (1) local stimulation-related deficits may be counteracted by boosting BMD between bilateral PFC, and that this effect should be (2) positively correlated with structural connectivity. Both predictions were confirmed; 5 Hz rTMS increased local success-related activity and local increases in PFC connectivity, while 1 Hz rTMS decreases local activity and triggered a more distributed pattern of bilateral PFC connectivity to compensate for this local inhibitory effect. These results provide an integrated, causal explanation for the network interactions associated with successful memory encoding in older adults. Hum Brain Mapp 38:5987-6004, 2017. © 2017 Wiley Periodicals, Inc.

Cross-hemispheric collaboration and segregation associated with task difficulty as revealed by structural and functional connectivity.

Although it is known that brain regions in one hemisphere may interact very closely with their corresponding contralateral regions (collaboration) or operate relatively independent of them (segregation), the specific brain regions (where) and conditions (how) associated with collaboration or segregation are largely unknown. We investigated these issues using a split field-matching task in which participants matched the meaning of words or the visual features of faces presented to the same (unilateral) or to different (bilateral) visual fields. Matching difficulty was manipulated by varying the semantic similarity of words or the visual similarity of faces. We assessed the white matter using the fractional anisotropy (FA) measure provided by diffusion tensor imaging (DTI) and cross-hemispheric communication in terms of fMRI-based connectivity between homotopic pairs of cortical regions. For both perceptual and semantic matching, bilateral trials became faster than unilateral trials as difficulty increased (bilateral processing advantage, BPA). The study yielded three novel findings. First, whereas FA in anterior corpus callosum (genu) correlated with word-matching BPA, FA in posterior corpus callosum (splenium-occipital) correlated with face-matching BPA. Second, as matching difficulty intensified, cross-hemispheric functional connectivity (CFC) increased in domain-general frontopolar cortex (for both word and face matching) but decreased in domain-specific ventral temporal lobe regions (temporal pole for word matching and fusiform gyrus for face matching). Last, a mediation analysis linking DTI and fMRI data showed that CFC mediated the effect of callosal FA on BPA. These findings clarify the mechanisms by which the hemispheres interact to perform complex cognitive tasks.

Less wiring, more firing: low-performing older adults compensate for impaired white matter with greater neural activity.

The reliable neuroimaging finding that older adults often show greater activity (over-recruitment) than younger adults is typically attributed to compensation. Yet, the neural mechanisms of over-recruitment in older adults (OAs) are largely unknown. Rodent electrophysiology studies have shown that as number of afferent fibers within a circuit decreases with age, the fibers that remain show higher synaptic field potentials (less wiring, more firing). Extrapolating to system-level measures in humans, we proposed and tested the hypothesis that greater activity in OAs compensates for impaired white-matter connectivity. Using a neuropsychological test battery, we measured individual differences in executive functions associated with the prefrontal cortex (PFC) and memory functions associated with the medial temporal lobes (MTLs). Using event-related functional magnetic resonance imaging, we compared activity for successful versus unsuccessful trials during a source memory task. Finally, we measured white-matter integrity using diffusion tensor imaging. The study yielded 3 main findings. First, low-executive OAs showed greater success-related activity in the PFC, whereas low-memory OAs showed greater success-related activity in the MTLs. Second, low-executive OAs displayed white-matter deficits in the PFC, whereas low-memory OAs displayed white-matter deficits in the MTLs. Finally, in both prefrontal and MTL regions, white-matter decline and success-related activations occurred in close proximity and were negatively correlated. This finding supports the less-wiring-more-firing hypothesis, which provides a testable account of compensatory over-recruitment in OAs.

The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults.

In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal (rsfMRI) has been proposed as an index of vascular reactivity. The RSFA compares favourably with other techniques such as breath-hold and hypercapnia, but the latter are more difficult to perform in some populations, such as older adults. The RSFA is therefore a candidate for use in adjusting for age-related changes in vascular reactivity in fMRI studies. The use of RSFA is predicated on its sensitivity to vascular rather than neural factors; however, the extent to which each of these factors contributes to RSFA remains to be characterized. The present work addressed these issues by comparing RSFA (i.e., rsfMRI variability) to proxy measures of (i) cardiovascular function in terms of heart rate (HR) and heart rate variability (HRV) and (ii) neural activity in terms of resting state magnetoencephalography (rsMEG). We derived summary scores of RSFA, a sensorimotor task BOLD activation, cardiovascular function and rsMEG variability for 335 healthy older adults in the population-based Cambridge Centre for Ageing and Neuroscience cohort (Cam-CAN; www.cam-can.com). Mediation analysis revealed that the effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. Furthermore, the converse effects of ageing on the rsMEG variability were not mediated by vascular factors. We then examined the effect of RSFA scaling of task-based BOLD in the sensorimotor task. The scaling analysis revealed that much of the effects of age on task-based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing. The results from the mediation analysis demonstrate that RSFA is modulated by measures of vascular function and is not driven solely by changes in the variance of neural activity. Based on these findings we propose that the RSFA scaling method is articularly useful in large scale and longitudinal neuroimaging studies of ageing, or with frail participants, where alternative measures of vascular reactivity are impractical.