Previous studies have shown that females typically outperform males on episodic memory tasks. In this study, we investigated if (1) there are differences between males and females in their connectome characteristics, (2) if these connectivity patterns are associated with memory performance, and (3) if these brain connectome characteristics contribute to the differences in episodic memory performance between sexes. In a sample of 655 healthy young subjects (n = 391 females; n = 264 males), we derived brain network characteristics from diffusion-weighted imaging (DWI) data using models of crossing fibers within each voxel of the brain and probabilistic tractography (graph strength, shortest path length, global efficiency, and weighted transitivity). Group differences were analysed with linear models and mediation analyses were used to explore how connectivity patterns might relate to sex-dependent differences in memory performance. Our results show significant sex-dependent differences in weighted transitivity (d = 0.42), with males showing higher values. Further, we observed a negative association between weighted transitivity and memory performance (r = -0.12). Finally, these distinct connectome characteristics partially mediated the observed differences in memory performance (effect size of the indirect effect r = 0.02). Our findings indicate a higher interconnectedness in females compared to males. Additionally, we demonstrate that the sex-dependent differences in episodic memory performance can be partially explained by the differences in this connectome measure. These results further underscore the importance of sex-dependent differences in brain connectivity and their impact on cognitive function.

The brain functional connectome forms a relatively stable and idiosyncratic backbone that can be used for identification or "fingerprinting" of individuals with a high level of accuracy. While previous cross-sectional evidence has demonstrated increased stability and distinctiveness of the brain connectome during the course of childhood and adolescence, less is known regarding the longitudinal stability in middle and older age. Here, we collected structural and resting-state functional MRI data at two time points separated by 2-3 years in 75 middle-aged and older adults (age 49-80, SD = 6.91 years) which allowed us to assess the long-term stability of the functional connectome. We show that the connectome backbone generally remains stable over a 2-3 years period in middle and older age. Independent of age, cortical volume was associated with the connectome stability of several canonical resting-state networks, suggesting that the connectome backbone relates to structural properties of the cortex. Moreover, the individual longitudinal stability of subcortical and default mode networks was associated with individual differences in cross-sectional and longitudinal measures of episodic memory performance, providing new evidence for the importance of these networks in maintaining mnemonic processing in middle and old age. Together, the findings encourage the use of within-subject connectome stability analyses for understanding individual differences in brain function and cognition in aging.

Βeta-amyloid (Aβ) is a neurotoxic protein that deposits early in the pathogenesis of preclinical Alzheimer's disease. We aimed to identify network connectivity that may alter the negative effect of Aβ on cognition. Following assessment of memory performance, resting-state fMRI, and mean cortical PET-Aβ, a total of 364 older adults (286 with clinical dementia rating [CDR-0], 59 with CDR-0.5 and 19 with CDR-1, mean age: 74.0 ± 6.4 years) from the OASIS-3 sample were included in the analysis. Across all participants, a partial least squares regression showed that lower connectivity between posterior medial default mode and frontoparietal networks, higher within-default mode, and higher visual-motor connectivity predict better episodic memory. These connectivities partially mediate the effect of Aβ on episodic memory. These results suggest that connectivity strength between the precuneus cortex and the superior frontal gyri may alter the negative effect of Aβ on episodic memory. In contrast, education was associated with different functional connectivity patterns. In conclusion, functional characteristics of specific brain networks may help identify amyloid-positive individuals with a higher likelihood of memory decline, with implications for AD clinical trials.

The neuroanatomical bases of episodic memory (EM) and executive functions (EFs) have been widely addressed in patients with brain damage and in individuals with neurologic disorders. These studies reported that larger brain structures support better outcomes in both cognitive domains, thereby supporting the "bigger is better" account. However, relatively few studies have explored the cerebral morphological properties underlying EM and EFs in cognitively healthy individuals and current findings indicate no unitary theoretical explanation for the structure-function relationship. Moreover, existing studies have typically restricted the analyses to a priori defined regions of interest. Here we conducted unbiased voxel-wise analysis of the associations between regional gray as well as white matter volumes (GMv; WMv) and performance in both cognitive domains in a sample of 463 cognitively intact individuals. We found that efficiency in EM was predicted by lower GMv in brain areas belonging to the default-mode network (DMN). By contrast, EFs performance was predicted by larger GMv in a distributed set of regions, which overlapped with the executive control network (ECN). Volume of white matter bundles supporting both cross-cortical and interhemispheric connections was positively related to processing speed. Furthermore, aging modulated the relationship between regional volumes and cognitive performance in several areas including the hippocampus and frontal cortex. Our data extend the critical role of the DMN and ECN by showing that variability in their morphological properties, and not only their activation patterns, affects EM and EFs, respectively. Moreover, our finding that aging reverts these associations supports previously advanced theories of cognitive neurodevelopment.

Recent neuroimaging and lesion studies have led to competing hypotheses for potential roles of the left lateral parietal lobe in episodic memory retrieval. These hypotheses may be dissociated by whether they imply a role in preretrieval or postretrieval processes. For example, one hypothesis is the left parietal cortex (particularly in more ventral subregions) forms part of an "episodic buffer" that supports the online representation of the retrieved target, a role that is, by definition, postretrieval. An alternate view maintains parietal activity (particularly in more dorsal subregions) contributes to top-down orientation of attention to retrieval search, a preretrieval role. The present investigation seeks to reveal the earliest onset of lateral parietal activity in three anatomically-defined subregions of the left lateral parietal cortex to identify any preretrieval activation. Subjects performed a pair-cued recall task while neural activity was recorded with magnetoencephalography (MEG) at millisecond temporal resolution. MEG data were then mapped to each subject's cortical surface using dynamic statistical parametric mapping (dSPM). Both dorsal and ventral regions showed retrieval-related activations beginning within ∼100 ms of the cue to retrieve and lasting up to 400 ms. We conclude that this early and transient pattern of activity in lateral parietal cortex is most consistent with a preretrieval role, possibly in directing attention to episodic memory retrieval.

The incidental acquisition of multimodal associations is a key memory function for everyday life. While the posterior parietal cortex has been frequently shown to be involved for these memory functions, ventral and dorsal regions revealed differences in their functional recruitment and the precise difference in multimodal memory processing with respect to the associative process has not been differentiated. Using an incidental multimodal learning task, we isolated the associative process during multimodal learning and recollection. The result of the present functional magnetic resonance imaging (fMRI) study demonstrated that during both learning and recollection a clear functional differentiation between ventral and dorsal posterior parietal regions was found and can be related directly to the associative process. The recruitment of a ventral region, the angular gyrus, was specific for learning and recollection of multimodal associations. In contrast, a dorsal region, the superior parietal lobule, could be attributed to memory guided attentional processing. Independent of the memory stage, we assumed a general role for the angular gyrus in the generation of associative representations and updating of fixed association, episodic memory.

We investigated the neural correlates supporting three kinds of memory judgments after very short delays using naturalistic material. In two functional magnetic resonance imaging (fMRI) experiments, subjects watched short movie clips, and after a short retention (1.5-2.5 s), made mnemonic judgments about specific aspects of the clips. In Experiment 1, subjects were presented with two scenes and required to either choose the scene that happened earlier in the clip ("scene-chronology"), or with a correct spatial arrangement ("scene-layout"), or that had been shown ("scene-recognition"). To segregate activity specific to seen versus unseen stimuli, in Experiment 2 only one probe image was presented (either target or foil). Across the two experiments, we replicated three patterns underlying the three specific forms of memory judgment. The precuneus was activated during temporal-order retrieval, the superior parietal cortex was activated bilaterally for spatial-related configuration judgments, whereas the medial frontal cortex during scene recognition. Conjunction analyses with a previous study that used analogous retrieval tasks, but a much longer delay (>1 day), demonstrated that this dissociation pattern is independent of retention delay. We conclude that analogous brain regions mediate task-specific retrieval across vastly different delays, consistent with the proposal of scale-invariance in episodic memory retrieval.

The reduction of neural activity in response to repeated stimuli, repetition suppression, is one of the most robust experience-related cortical dynamics known to cognitive neuroscience. Functional magnetic resonance imaging (fMRI) studies during episodic memory encoding have demonstrated repetition suppression in the hippocampus and this reduction has been linked to successful memory formation. An emerging body of functional imaging evidence suggests that the posteromedial cortex, in addition to the medial temporal lobes, may have a pivotal role in successful episodic memory. This area typically deactivates during initial memory encoding, but its functional changes in response to repetitive encoding remain poorly specified. Here, we investigate the repetition-related changes in the posteromedial cortex as well as the hippocampus while the participants underwent an fMRI experiment involving repetitive encoding of face-name pairs. During the first encoding trial of face-name pairs, significant activation in the hippocampus was observed. The second and third encoding trials demonstrated a repetition suppression effect in the hippocampus, indicated by a stepwise decrease of activation. In contrast, the posteromedial cortex demonstrated significant deactivation during the initial encoding trial of face-name pairs. The second and third encoding trials demonstrated a stepwise decrease of deactivation, repetition enhancement, with activity at or above baseline levels in the final encoding trial. These findings demonstrate that hippocampus repetition suppression as well as posteromedial repetition enhancement is related to successful encoding processes and are discussed in relation to the default mode hypothesis as well as potential implications for understanding late-life amnestic disorders.

Memory-related functional magnetic resonance imaging (fMRI) activations show age-related differences across multiple brain regions that can be captured in summary statistics like single-value scores. Recently, we described two single-value scores reflecting deviations from prototypical whole-brain fMRI activity of young adults during novelty processing and successful encoding. Here, we investigate the brain-behavior associations of these scores with age-related neurocognitive changes in 153 healthy middle-aged and older adults. All scores were associated with episodic recall performance. The memory network scores, but not the novelty network scores, additionally correlated with medial temporal gray matter and other neuropsychological measures including flexibility. Our results thus suggest that novelty-network-based fMRI scores show high brain-behavior associations with episodic memory and that encoding-network-based fMRI scores additionally capture individual differences in other aging-related functions. More generally, our results suggest that single-value scores of memory-related fMRI provide a comprehensive measure of individual differences in network dysfunction that may contribute to age-related cognitive decline.

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for "what," reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the "where" component for hippocampal episodic memory and for spatial navigation. The dorsal-transitional-visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for "what," reward, and "where" scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions.

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803-814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age-group-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.

The default mode network (DMN) typically exhibits deactivations during demanding tasks compared to periods of relative rest. In functional magnetic resonance imaging (fMRI) studies of episodic memory encoding, increased activity in DMN regions even predicts later forgetting in young healthy adults. This association is attenuated in older adults and, in some instances, increased DMN activity even predicts remembering rather than forgetting. It is yet unclear whether this phenomenon is due to a compensatory mechanism, such as self-referential or schema-dependent encoding, or whether it reflects overall reduced DMN activity modulation in older age. We approached this question by systematically comparing DMN activity during successful encoding and tonic, task-independent, DMN activity at rest in a sample of 106 young (18-35 years) and 111 older (60-80 years) healthy participants. Using voxel-wise multimodal analyses, we assessed the age-dependent relationship between DMN resting-state amplitude (mean percent amplitude of fluctuation, mPerAF) and DMN fMRI signals related to successful memory encoding, as well as their modulation by age-related hippocampal volume loss, while controlling for regional grey matter volume. Older adults showed lower resting-state DMN amplitudes and lower task-related deactivations. However, a negative relationship between resting-state mPerAF and subsequent memory effect within the precuneus was observed only in young, but not older adults. Hippocampal volumes showed no relationship with the DMN subsequent memory effect or mPerAF. Lastly, older adults with higher mPerAF in the DMN at rest tend to show higher memory performance, pointing towards the importance of a maintained ability to modulate DMN activity in old age.

Neuropsychological test is an essential tool in assessing cognitive and functional changes associated with late-life neurocognitive disorders. Despite the utility of the neuropsychological test, the brain-wide neural basis of the test performance remains unclear. Using the predictive modeling approach, we aimed to identify the optimal combination of functional connectivities that predicts neuropsychological test scores of novel individuals. Resting-state functional connectivity and neuropsychological tests included in the OASIS-3 dataset (n = 428) were used to train the predictive models, and the identified models were iteratively applied to the holdout internal test set (n = 216) and external test set (KSHAP, n = 151). We found that the connectivity-based predicted score tracked the actual behavioral test scores (r = 0.08-0.44). The predictive models utilizing most of the connectivity features showed better accuracy than those composed of focal connectivity features, suggesting that its neural basis is largely distributed across multiple brain systems. The discriminant and clinical validity of the predictive models were further assessed. Our results suggest that late-life neuropsychological test performance can be formally characterized with distributed connectome-based predictive models, and further translational evidence is needed when developing theoretically valid and clinically incremental predictive models.

Hippocampal changes are associated with increased age and cognitive decline due to mild cognitive impairment (MCI) and Alzheimer's disease (AD). These associations are often observed only in the later stages of decline. This study examined if hippocampal grading, a method measuring local morphological similarity of the hippocampus to cognitively normal controls (NCs) and AD participants, is associated with cognition in NCs, subjective cognitive decline (SCD), early (eMCI), late (lMCI), and AD. A total of 1620 Alzheimer's Disease Neuroimaging Initiative participants were examined (495 NC, 262 eMCI, 545 lMCI, and 318 AD) because they had baseline MRIs and Alzheimer's disease Assessment Scale (ADAS-13) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. In a sub-analysis, NCs with episodic memory scores (as measured by Rey Auditory Verbal Learning Test, RAVLT) were divided into those with subjective cognitive decline (SCD+; 103) and those without (SCD-; 390). Linear regressions evaluated the influence of hippocampal grading on cognition in preclinical and prodromal AD. Lower global cognition, as measured by increased ADAS-13, was associated with hippocampal grading: NC (p < .001), eMCI (p < .05), lMCI (p < .05), and AD (p = .01). Lower global cognition as measured increased CDR-SB was associated with hippocampal grading in lMCI (p < .05) and AD (p < .001). Lower RAVLT performance was associated with hippocampal grading in SCD- (p < .05) and SCD+ (p < .05). These findings suggest that hippocampal grading is associated with global cognition in NC, eMCI, lMCI, and AD. Early changes in episodic memory during pre-clinical AD are associated with changes in hippocampal grading. Hippocampal grading may be sensitive to progressive changes early in the disease course.

The majority of patients with temporal lobe epilepsy (TLE) experience disturbances of episodic memory from structural damage or dysfunction of the hippocampus. The objective of this study was to use functional Magnetic Resonance Imaging (fMRI) to identify regions where resting state connectivity to the left hippocampus (LH) is correlated with neuropsychological measures of verbal memory retention in TLE patients. Eleven left TLE (LTLE) patients and 15 control subjects participated in resting state fMRI scans. All LTLE patients underwent neuropsychological testing. Resting state functional connectivity maps to the LH were calculated for each patient, and subsequently used in a multiple regression analysis with verbal memory retention scores as a covariate. The analysis identified brain regions whose connectivity to the LH was linearly related to memory retention scores across the group of patients. In LTLE patients, right sided (contralateral) clusters in the precuneus and inferior parietal lobule (IPL) exhibited increased connectivity to the LH with increased memory retention score; left sided (ipsilateral) regions in the precuneus and IPL showed increased connectivity to the LH with decreased retention score. Patients with high memory retention scores had greater connectivity between the LH-right parietal clusters than between the LH-left parietal clusters; in contrast, control subjects had significantly and consistently greater LH-left hemisphere than LH-right hemisphere connectivity. Our results suggest that increased connectivity in contralateral hippocampal functional pathways within the episodic verbal memory network represents a strengthening of alternative pathways in LTLE patients with strong verbal memory retention abilities.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

The posterior midline region (PMR)-considered a core of the default mode network-is deactivated during successful performance in different cognitive tasks. The extent of PMR-deactivations is correlated with task-demands and associated with successful performance in various cognitive domains. In the domain of episodic memory, functional MRI (fMRI) studies found that PMR-deactivations reliably predict learning (successful encoding). Yet it is unclear what explains this relation. One intriguing possibility is that PMR-deactivations are partially mediated by respiratory artifacts. There is evidence that the fMRI signal in PMR is particularly prone to respiratory artifacts, because of its large surrounding blood vessels. As respiratory fluctuations have been shown to track changes in attention, it is critical for the general interpretation of fMRI results to clarify the relation between respiratory fluctuations, cognitive performance, and fMRI signal. Here, we investigated this issue by measuring respiration during word encoding, together with a breath-holding condition during fMRI-scanning. Stimulus-locked respiratory analyses showed that respiratory fluctuations predicted successful encoding via a respiratory phase-locking mechanism. At the same time, the fMRI analyses showed that PMR-deactivations associated with learning were reduced during breath-holding and correlated with individual differences in the respiratory phase-locking effect during normal breathing. A left frontal region--used as a control region--did not show these effects. These findings indicate that respiration is a critical factor in explaining the link between PMR-deactivation and successful cognitive performance. Further research is necessary to demonstrate whether our findings are restricted to episodic memory encoding, or also extend to other cognitive domains.

The "brain signature of cognition" concept has garnered interest as a data-driven, exploratory approach to better understand key brain regions involved in specific cognitive functions, with the potential to maximally characterize brain substrates of behavioral outcomes. Previously we presented a method for computing signatures of episodic memory. However, to be a robust brain measure, the signature approach requires a rigorous validation of model performance across a variety of cohorts. Here we report validation results and provide an example of extending it to a second behavioral domain. In each of two discovery data cohorts, we derived regional brain gray matter thickness associations for two domains: neuropsychological and everyday cognition memory. We computed regional association to outcome in 40 randomly selected discovery subsets of size 400 in each cohort. We generated spatial overlap frequency maps and defined high-frequency regions as "consensus" signature masks. Using separate validation datasets, we evaluated replicability of cohort-based consensus model fits and explanatory power by comparing signature model fits with each other and with competing theory-based models. Spatial replications produced convergent consensus signature regions. Consensus signature model fits were highly correlated in 50 random subsets of each validation cohort, indicating high replicability. In comparisons over each full cohort, signature models outperformed other models. In this validation study, we produced signature models that replicated model fits to outcome and outperformed other commonly used measures. Signatures in two memory domains suggested strongly shared brain substrates. Robust brain signatures may therefore be achievable, yielding reliable and useful measures for modeling substrates of behavioral domains.

The goal of this project was to utilize an information theoretic formalism for medical image analysis initially proposed in [Young et al. (2005): Phys Rev Lett 94:098701-1] to detect and quantify subtle global and regional differences in spatial patterns in patients suffering from Alzheimer's disease (AD) and frontotemporal dementia (FTD) by estimating the structural complexity of anatomical brain MRI. The sensitivity and specificity of the results are compared with those of a recent analysis, currently considered state of the art for MR studies of neurodegeneration. The previous study used regional estimates of cortical thinning and/or volume loss to differentiate between normal aging, AD, and FTD. The analysis illustrates that the structural complexity estimation method, a general multivariate approach to the study of variation in brain structure which does not depend on highly specialized volumetric and thickness estimates, is capable of providing sensitive and interpretable diagnostic information.

White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle-aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS-IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion-weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel-wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)-ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle-aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.