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Werkle-Bergner, M.

Publications and source records attributed to Werkle-Bergner, M..

At least 19 recordsLinked to original sources

Infantile amnesia results from differential memory retrieval in humans

Infantile amnesia, the inability to recall memories from our earliest years, is the most common form of forgetting in mammals. Whether early memories never form, decay, or persist but become inaccessible remains unknown. Here, we investigated the nature of forgetting during the infantile amnesia period by longitudinally testing toddlers aged 18-24 months across the complete memory cycle from encoding, initial retrieval one day later, and delayed retrieval up to six months later, in a novel naturalistic episodic memory paradigm. Computational modelling revealed that forgetting during the infantile amnesia period was heterogeneous. Toddlers were as likely to retain the full memory as to lose it completely, while nearly a quarter retained only part of the memory. Encoding accuracy predicted which toddlers retained the full memory at the test one day later, but not at the delayed test up to six months on. Instead, a retrieval-specific EEG signature predicted complete, but not partial, memory retrieval, distinguishing which toddlers had retained the full memory before their behavioural response. Finally, leveraging the COVID-19 pandemic as a natural experiment, we found that maternal immune activation during pregnancy, as in rodents, alters vulnerability to infantile forgetting in humans. Together, these findings show that early memories formed during the infantile amnesia period are not simply erased but persist in an increasingly inaccessible form, a transformation whose trajectory can be shaped by both the neural retrieval mechanism and the prenatal environment.

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Capturing the developing brain in motion: A practical tutorial for recording mobile EEG in naturally moving children

This tutorial seeks to facilitate the use of mobile electroencephalography (EEG) in young children. Mobile EEG allows researchers to investigate neural correlates of behavioral and cognitive processes in ecologically valid settings. While mobile EEG has been widely adopted in adult research, studies applying it to freely moving children remain scarce. However, investigating neural processes during active behavior and in interaction with movement is indispensable for advancing our understanding of neural correlates of cognitive development in early childhood. Here, we provide a practical tutorial on the collection and preprocessing of mobile EEG data from children. Drawing on experience and data from a large-scale study with toddlers, we summarize key methodological considerations, discuss common challenges and practical recommendations, and present a preprocessing pipeline developed for developmental mobile EEG data. In addition, we provide example EEG datasets from naturally moving 18-20-month-old toddlers. We argue that incorporating mobile EEG into developmental cognitive neuroscience allows researchers to (i) investigate cognitive development in naturalistic environments, (ii) examine associations among bodily movement, neural activity, and behavior, and (iii) study samples that are difficult to reach with stationary research. HighlightsO_LIMobile EEG enables investigation of neural processes during active behavior C_LIO_LIMobile EEG in moving freely children comes with unique methodological challenges C_LIO_LIWe provide practical recommendations for developmental mobile EEG studies C_LIO_LIA dataset and preprocessing pipeline from a toddler mobile EEG study are provided C_LI

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Neocortical differentiation and hippocampal integration of non-meaningful items and their spatial location

Computational theories of memory posit that the dentate gyrus and CA3 (CA3DG) hippocampal subfields reduce mnemonic interference via a process called pattern separation. While the CA3DG is viewed as a domain-general pattern separator, the parahippocampal and perirhinal cortices may play a role in content-specific (e.g., spatial or object-related) interference reduction. Recent work highlighted the role of frontal and parietal control areas in allocating resources during mnemonic discrimination, but the interactions between the medial temporal lobe and frontoparietal regions have been rarely studied. Moreover, mnemonic discrimination tasks designed for humans almost exclusively use everyday items as stimuli, confounding retrieval processes with pattern separation. To address these challenges we acquired high-resolution structural images of the medial temporal lobe, and full-brain high-resolution functional MRI data of 39 participants while they studied non-meaningful fractals with varying degrees of interference in either their spatial or object features. We found that the parahippocampal cortex contributes to interference reduction in the spatial domain, while the perirhinal cortex contributes to interference reduction in the object domain. The dorsolateral frontal and parietal regions were recruited during the encoding of interfering stimuli in both object and location domains, and displayed strengthened within- and cross-network connectivity in response to interference. Contrary to our expectations, we did not find significantly increased activation in the CA3DG to similar trials relative to repeats, indicating a lack of sensitivity to small differences in interfering stimuli. Altogether, these results are in line with content-specific interference reduction in the medial temporal lobe, possibly orchestrated by frontoparietal regions, but challenge the view of the CA3DG as the universal pattern separator of the human brain.

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Age differences in neural distinctiveness during memory retrieval versus reinstatement

Robust evidence points to mnemonic deficits in older adults related to dedifferentiated, i.e., less distinct, neural responses during memory encoding. However, less is known about retrieval-related dedifferentiation and its role in age-related memory decline. In this study, younger and older adults were scanned both while incidentally learning face and house stimuli and while completing a surprise recognition memory test. Using pattern similarity searchlight analyses, we looked for indicators of neural dedifferentiation during retrieval and asked whether this might explain interindividual differences in memory performance. Our findings revealed age-related reductions in neural distinctiveness during memory retrieval as well as in encoding-retrieval reinstatement in visual processing regions. We further demonstrated that the degree to which patterns elicited during encoding were reinstated during retrieval tracked variability in memory performance better than retrieval-related distinctiveness only. All in all, we contribute to meager existing evidence for age-related neural dedifferentiation during memory retrieval. We propose that the recognition task (as opposed to a cued recall task) may have revealed impairment in perceptual processing in older adults, leading to particularly widespread age differences in neural distinctiveness. We additionally provide support for the idea that well-defined reactivation of encoding patterns plays a major role in successful memory retrieval.

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The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance

Researchers have identified changes in dopaminergic neuromodulation as playing a key role in adult memory decline. Facilitated by technical advancements, recent research has also implicated noradrenergic neuromodulation in shaping late-life memory performance. However, it is not yet clear whether these two neuromodulators have distinct roles in age-related cognitive changes. Combining longitudinal high-resolution magnetic resonance imaging of the dopaminergic substantia nigra-ventral tegmental area (SN-VTA) and the noradrenergic locus coeruleus (LC) in younger (n = 69) and older adults (n = 251), we found that dopaminergic and noradrenergic integrity are differentially associated with individual differences in memory performance. While LC integrity was related to better episodic memory across several memory tasks, SN-VTA integrity was linked to working memory. Moreover, consistent with their dense interconnection and a largely shared biosynthesis, dopaminergic and noradrenergic brain regions integrity were positively related, and correlated with medial temporal lobe volumes. Longitudinally, we found that older age was associated with more-negative change in SN- VTA and LC integrity (time point 1-time point 2; mean delay [~]1.9 years). Importantly, changes in LC integrity reliably predicted future episodic memory performance (at time point 3). These findings support the feasibility of in-vivo indices for catecholaminergic integrity with potential clinical utility, given the degeneration of both neuromodulatory systems in several age-associated diseases. Moreover, they highlight differential roles of dopaminergic and noradrenergic neuromodulatory nuclei in late-life cognitive decline.

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Sleep spindle maturation enhances slow oscillation-spindle coupling

The synchronization of canonical fast sleep spindle activity (12.5-16 Hz) precisely during the slow oscillation up peak is considered an essential feature of adult non-rapid eye movement sleep. However, there is little knowledge on how this well-known coalescence between slow oscillations and sleep spindles develops. Leveraging individualized detection of single events, we first provide a detailed cross-sectional characterization of age-specific patterns of slow and fast sleep spindles, slow oscillations, and their coupling in children aged 5 to 6, 8 to 11, and 14 to 18 years. Critically, based on this, we then investigated how spindle and slow oscillation maturity substantiate age differences in their precise orchestration. While the predominant type of fast spindles was development-specific in that it was still nested in a frequency range below the canonical fast spindle range for the majority of children, the well-known slow oscillation-spindle coupling pattern was evident for sleep spindles in the canonical (adult-like) fast spindle range in all three age groups - but notably less precise in children. To corroborate these findings, we linked personalized measures of fast spindle maturity, which indicate the similarity between the prevailing development-specific and adult-like fast spindles, and slow oscillation maturity, which reflects the extent to which slow oscillations show frontal dominance, with individual slow oscillation-spindle coupling patterns. Importantly, we found that fast spindle maturity was uniquely associated with enhanced slow oscillation-spindle coupling strength and precision. Taken together, our results suggest that the increasing ability to generate canonical fast sleep spindles actuates precise slow oscillation-spindle coupling patterns across child and adolescent development.

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Age Differences in Diffusivity in the Locus Coeruleus and its Ascending Noradrenergic Tract

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used three datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220, and Stockholm Sleepy Brain, N = 49), to replicate published findings and expand them by investigating diffusivity in the LCs ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LCs ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to microstructural changes in aging that have opposing effects on fractional anisotropy. HighlightsO_LIFractional anisotropy in the locus coeruleus was lower in younger adults C_LIO_LIFractional anisotropy in the noradrenergic bundle was higher in younger adults C_LIO_LISleep deprivation may affect diffusivity in younger adults more than older adults C_LI

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Age-related declines in neural selectivity manifest differentially during encoding and recognition

The authors have withdrawn the preprint due to two errors in the analyses: The first error was a failure to account for three dummy volumes (TR = 2s) collected at the beginning of each experimental run. The second error was a coding error related to the definition of the category-selective clusters. Since correcting for these errors drastically altered the results and conclusions of this paper, the authors have withdrawn the preprint and retracted the published paper (https://doi.org/10.1016/j.neurobiolaging.2021.12.001). A report comparing original and corrected results can be found on https://osf.io/7n3mz/. If you have any questions please contact the corresponding author (sander@mpib-berlin.mpg.de).

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Memory specificity is linked to repetition effects in event-related potentials across the lifespan

The specificity with which past experiences can be remembered varies across the lifespan, possibly due to differences in how precisely information is encoded. Memory formation can be investigated through repetition effects, the common finding that neural activity is altered when stimuli are repeated. However, whether differences in this indirect measure of memory formation relate to lifespan differences in memory specificity has not yet been established. In the present study, we examined repetition effects in event-related potentials and their relation to recognition. During incidental encoding, children (aged 7-9 years), young adults (18-30 years), and older adults (65-76 years) viewed repeated object images from different categories. During subsequent recognition, we distinguished memory for the specific items versus the general categories. We identified repetition suppression in all age groups, and repetition enhancement for adults. Furthermore, individual item recognition performance comprising lure discrimination was positively associated with the magnitude of the neural repetition effects, which did not differ between groups, indicating common neural mechanisms of memory formation. Our findings demonstrate that neural repetition effects reflect the formation of highly specific memory representations and highlight their significance as a neural indicator of individual differences in episodic memory encoding across the lifespan.

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Electrophysiological Indicators of Sleep-associated Memory Consolidation in 5- to 6-year-old Children

In adults, the synchronised interplay of sleep spindles (SP) and slow oscillations (SO) supports memory consolidation. Given tremendous developmental changes in SP and SO morphology, it remains elusive whether across childhood the same mechanisms as identified in adults are functional. Based on topography and frequency, we characterise slow and fast SPs and their temporal coupling to SOs in 24 pre-school children. Further, we ask whether slow and fast SPs and their modulation during SOs are associated with behavioural indicators of declarative memory consolidation as suggested by the literature on adults. Employing an individually tailored approach, we reliably identify an inherent, development-specific fast centro-parietal SP type, nested in the adult-like slow SP frequency range, along with a dominant slow frontal SP type. Further, we provide evidence that the modulation of fast centro-parietal SPs during SOs is already present in pre-school children. However, the temporal coordination between fast centro-parietal SPs and SOs is weaker and less precise than expected from research on adults. While we do not find evidence for a critical contribution of SP-SO coupling for memory consolidation, crucially, slow frontal and fast centro-parietal SPs are each differentially related to sleep-associated consolidation of items of varying quality. While a higher number of slow frontal SPs is associated with stronger maintenance of medium-quality memories, a higher number of fast centro-parietal SPs is linked to a greater gain of low-quality items. Our results demonstrate two functionally relevant inherent SP types in pre-school children although SP-SO coupling is not yet fully mature.

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Tracking age differences in neural distinctiveness across representational levels

The authors have withdrawn the preprint due to two errors in the analyses: The first error was a failure to account for three dummy volumes (TR = 2s) collected at the beginning of each experimental run. The second error was a coding error related to the definition of the category-selective clusters. Since correcting for these errors drastically altered the results and conclusions of this paper, the authors have withdrawn the preprint and retracted the published paper. More information as well as a report comparing original and corrected results can be found on https://osf.io/t8dpv/. If you have any questions please contact the corresponding author (sander@mpib-berlin.mpg.de).

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Locus coeruleus MRI contrast is associated with cortical thickness in older adults

There is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in older (n = 229) and younger adults (n = 67). Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The Freesurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.

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Studying the interplay of sleep and aging: Methodological challenges

In quest of new avenues to explain, predict, and treat pathophysiological conditions during aging, research on sleep and aging has flourished. Despite the great scientific potential to pinpoint mechanistic pathways between sleep, aging, and pathology, only little attention has been paid to the suitability of analytic procedures applied to study these interrelations. On the basis of electrophysiological sleep and structural brain data of healthy younger and older adults, we identify, illustrate, and resolve methodological core challenges in the study of sleep and aging. We demonstrate potential biases in common analytic approaches when applied to older populations. We argue that uncovering age-dependent alterations in the physiology of sleep requires the development of adjusted and individualized analytic procedures that filter out age-independent inter-individual differences. Age-adapted methodological approaches are thus required to foster the development of valid and reliable biomarkers of age-associated cognitive pathologies.

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Age Differences in Hemispheric Lateralization in Spatial and Verbal Visual Working Memory

Due to hemispheric specialization of the human brain, neural signatures of visual working memory (WM) performance are expected to differ between tasks involving verbal versus spatial memoranda. Theories of cognitive aging suggest a reduction of hemispheric specialization in older adults. Using behavioral and neural WM capacity markers, we assessed hemispheric lateralization in younger and older adults performing a spatial or verbal visual WM task. Participants encoded information presented in the left or right hemifield. We observed behavioral advantages for spatial stimuli processed in the right hemisphere and for verbal stimuli processed in the left hemisphere. While younger adults showed lateralization in both tasks, older adults showed lateralization only in the verbal task. Lateralization was assessed by the contralateral delay activity (CDA) on the neural level. CDA amplitudes displayed hemispheric lateralization for verbal versus spatial material, but this effect was age-invariant. While our findings support right-hemispheric specialization for spatial information maintenance, and left-hemispheric specialization for verbal information maintenance, we could not confirm a generalized reduction in hemispheric lateralization at older ages.

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Noradrenergic responsiveness preserves selective attention across the adult life span

Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in non-invasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a non-invasive marker of phasic norepinephrine (NE) release, while concurrently recording the electroencephalogram (EEG), of younger (N=39[male]; 25.2{+/-}3.2 years) and older adults (N=38[male]; 70.6{+/-}2.7 years). NE release was triggered on a trial-by-trial basis using fear-conditioned (CS+) stimuli. During conditioning, pupil and EEG markers related to heightened NE activity were identified. Afterwards, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears. During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired fear response, as reflected in pupil and EEG alpha-beta-band responses. Critically, pupil dilation to CS+ was correlated with stronger EEG alpha-beta desynchronization, suggesting a common dependence on NE release. On a behavioral level, NE release facilitated attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the life span. Significance statementIn old age the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants noradrenergic system while recording pupillometry and electroencephalography (EEG) to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups a more responsive noradrenergic system was strongly associated to attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late life cognition.

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Memory quality modulates the effect of aging on memory consolidation during sleep: Reduced maintenance but intact gain

Successful consolidation of associative memories relies on the coordinated interplay of slow oscillations and sleep spindles during non-rapid eye movement (NREM) sleep, enabling the transfer of labile information from the hippocampus to permanent memory stores in the neocortex. During senescence, the decline of the structural and functional integrity of the hippocampus and neocortical regions is paralleled by changes of the physiological events that stabilize and enhance associative memories during NREM sleep. However, the currently available evidence is inconclusive if and under which circumstances aging impacts memory consolidation. By tracing the encoding quality of single memories in individual participants, we demonstrate that previous learning determines the extent of age-related impairments in memory consolidation. Specifically, the detrimental effects of aging on memory maintenance were greatest for mnemonic contents of medium encoding quality, whereas memory gain of weakly encoded memories did not differ by age. Using multivariate techniques, we identified profiles of alterations in sleep physiology and brain structure characteristic for increasing age. Importantly, while both aged sleep and aged brain structure profiles were associated with reduced memory maintenance, inter-individual differences in neither sleep nor structural brain integrity qualified as the driving force behind age differences in sleep-dependent consolidation in the present study.

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Oscillatory Mechanisms of Successful Memory Formation in Younger and Older Adults Are Related to Structural Integrity

We studied oscillatory mechanisms of successful memory formation in 47 younger and 52 older adults in an intentional associative memory task with cued recall. While older adults showed reduced memory performance, we found subsequent memory effects (SME) in alpha/beta and theta frequency bands in both age groups. Using logistic mixed effect models, we then investigated whether interindividual differences in structural integrity of memory regions that were functionally linked to oscillatory dynamics in previous studies (Hanslmayr et al., 2011) could account for interindividual differences in the strength of the SME. Structural integrity of inferior frontal gyrus (IFG) and hippocampus (HC) was reduced in older adults. SME in the alpha/beta band were indeed modulated by the cortical thickness of inferior frontal gyrus (IFG), in line with its hypothesized role for deep semantic elaboration. Importantly, this structure-function relationship did not differ by age group. However, older adults were more frequently represented among the participants with low cortical thickness and consequently weaker SME in the alpha band. Thus, our results suggest that differences in the structural integrity of the IFG are the basis not only for interindividual, but also for age differences in memory formation.

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Neural pattern similarity differentially affects memory performance of younger and older adults

Age-related memory decline is associated with changes in neural functioning but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age, memory studies have shown that high similarity between activity patterns benefits memory performance for the respective stimuli. Here, we addressed this apparent conflict by investigating between-item representational similarity in 50 younger (19-27 years old) and 63 older (63-75 years old) human adults (male and female) who studied scene-word associations using a mnemonic imagery strategy while electroencephalography was recorded. We compared the similarity of spatiotemporal frequency patterns elicited during encoding of items with different subsequent memory fate. Compared to younger adults, older adults memory representations were more similar to each other but items that elicited the most similar activity patterns early in the encoding trial were those that were best remembered by older adults. In contrast, young adults memory performance benefited from decreased similarity between earlier and later periods in the encoding trials, which might reflect their better success in forming unique memorable mental images of the joint picture-word pair. Our results advance the understanding of the representational properties that give rise to memory quality as well as how these properties change in the course of aging. Significance statementDeclining memory abilities are one of the most evident limitations for humans when growing older. Despite recent advances of our understanding of how the brain represents and stores information in distributed activation patterns, little is known about how the quality of information representation changes during aging and thus affects memory performance. We investigated how the similarity between neural representations relates to subsequent memory quality in younger and older adults. We present novel evidence that the interaction of pattern similarity and memory performance differs between age groups: Older adults benefited from increased similarity during early encoding whereas young adults benefited from decreased similarity between early and later encoding. These results provide insights into the nature of memory and age-related memory deficits.

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