Study protocol of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA).

Background and purpose:

Neuro­cog­nitive aging and the associated brain diseases impose a major social and economic burden. Therefore, substantial efforts have been put into revealing the lifestyle, the neurobiological and the genetic underpinnings of healthy neurocognitive aging. However, these studies take place almost exclusively in a limited number of highly-developed countries. Thus, it is an important open question to what extent their findings may generalize to neurocognitive aging in other, not yet investigated regions. The purpose of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA) is to collect multi-modal longitudinal data on healthy neurocognitive aging to address the data gap in this field in Central and Eastern Europe.

We adapted the Australian Ima­ging, Biomarkers and Lifestyle (AIBL) study of aging study protocol to local circumstances and collected demographic, lifestyle, men­tal and physical health, medication and medical history related information as well as re­cor­ded a series of magnetic resonance imaging (MRI) data. In addition, participants were al­so offered to participate in the collection of blood samples to assess circulating in­flam­matory biomarkers as well as a sleep study aimed at evaluating the general sleep quality based on multi-day collection of subjective sleep questionnaires and whole-night elec­troencephalographic (EEG) data.

Baseline data collection has al­ready been accomplished for more than a hundred participants and data collection in the se­cond
session is on the way. The collected data might reveal specific local trends or could also indicate the generalizability of previous findings. Moreover, as the HuBA protocol al­so offers a sleep study designed for tho­rough characterization of participants’ sleep quality and related factors, our extended multi-modal dataset might provide a base for incorporating these measures into healthy and clinical aging research. 

Besides its straightforward na­tional benefits in terms of health ex­pen­di­ture, we hope that this Hungarian initiative could provide results valid for the whole Cent­ral and Eastern European region and could also promote aging and Alzheimer’s disease research in these countries.

A daytime nap with REM sleep is linked to enhanced generalization of emotional stimuli.

How memory representations are shaped during and after their encoding is a central question in the study of human memory. Recognition responses to stimuli that are similar to those observed previously can hint at the fidelity of the memories or point to processes of generalization at the expense of precise memory representations. Experimental studies utilizing this approach showed that emotions and sleep both influence these responses. Sleep, and more specifically rapid eye movement sleep, is assumed to facilitate the generalization of emotional memories. We studied mnemonic discrimination by the emotional variant of the Mnemonic Separation Task in participants (N = 113) who spent a daytime nap between learning and testing compared with another group that spent an equivalent time awake between the two sessions. Our findings indicate that the discrimination of similar but previously not seen items from previously seen ones is enhanced in case of negative compared with neutral and positive stimuli. Moreover, whereas the sleep and the wake groups did not differ in memory performance, participants entering rapid eye movement sleep exhibited increased generalization of emotional memories. Our findings indicate that entering into rapid eye movement sleep during a daytime nap shapes emotional memories in a way that enhances recognition at the expense of detailed memory representations.

[Verbal Episodic Memory Test]. / A Verbális Epizodikus Memória Teszt.

Background and purpose:

The decline of episodic memory is one of the earliest cognitive markers of mild cognitive impairment and various types of dementia. Until today, however, there is no standardized Hun­garian episodic memory test that takes into account the characteristics of the Hungarian language. The study presents the structure and standardized use of a new memory test (Verbal Episodic Memory Test, VEMT) as well as normative data in Hungary. 

The VEMT is suitable for the comprehensive examination of verbal learning abilities in a broader sense, and more specifically, for the neuropsychological measurement of verbal list learning abilities. In the present study, we constructed a normative database consisting of data from 385 participants.

We showed that the VEMT is sensitive to demographic factors (e.g., age) which are linked to differences in episodic memory performance. Open access to the test is provided, and the normative scores are presented as well. 

The indicators of the test are suitable for drawing a learning curve, for showing the interaction of new and previously learned information (interference effects), and for measuring differences between free recall and cued recall. Furthermore, the test scores are appropriate for distinguishing the effects of different types of memory encoding forms (phonological, semantic, and episodic), for measuring the ability to reconstruct the presentation of a sequence (memory order information), for detecting the rate of forgetting, for measuring recognition abilities, and for detecting hippocampus-related mnemonic pattern separation and completion functions. 

Positive schizotypy is associated with amplified mnemonic discrimination and attenuated generalization.

Tendency to experience inaccurate beliefs alongside perceptual anomalies constitutes positive schizotypal traits in the general population and shows continuity with the positive symptoms of schizophrenia. It has been hypothesized that the positive symptomatology of schizophrenia, and by extension, the odd beliefs and unusual perceptual experiences in the general population, are associated with specific alterations in memory functions. An imbalance between memory generalization and episodic memory specificity has been proposed on several counts; however, the direction of the imbalance is currently unclear. Here, we evaluated the association between positive schizotypy, and memory alterations related to hippocampal computations in a general population sample enriched for positive schizotypy. We found that memory generalization is attenuated while memory specificity is elevated in participants with more pronounced positive schizotypal traits. Our findings show that people who are prone to irrational beliefs and unusual experiences also show measurable alterations in memory and likely have difficulty grasping the global picture and rather be overpowered by fragments of information.

Litmus test of rich episodic representations: Context-induced false recognition.

Context-dependent episodic memory is typically investigated using tasks in which retrieval occurs either in the reinstated context of encoding or in a completely new context. A fundamental question of episodic memory models is the level of detail in episodic memory representations containing contextual information about the encoded event. The present study examined whether memory is affected when the contexts of encoding and retrieval are highly similar but not exactly the same. At encoding, participants saw unique object images presented on the background of unique context scene images. On a surprise recognition test, the objects were either old or visually similar to ones seen at encoding (lure stimuli). The objects were presented on either the old or a lure context image; the lure context image was visually similar to the corresponding object's encoding context. Context reinstatement increased the hit rate for the old objects, but also increased the false alarm for the lure objects. This latter finding indicates that the presence of the encoding context at test does not always aid recognition memory decisions. These results suggest that slight visual differences between the contexts of encoding and retrieval matter, as context reinstatement leads to a tendency to respond Old even in case of small differences in the old and lure contexts.

People sometimes remember to forget: Strategic retrieval from the list before last enables directed forgetting of the most recent information.

List-method directed forgetting usually involves asking people to study a list, followed by a cue to forget it, and then studying a second list. Prior work suggests that List 2 encoding is necessary for directed forgetting to occur, but recent studies have found that moving the forget cue from List 1 to List 2 allows people to selectively forget List 2. These results were attributed to an inhibitory mechanism. In four experiments, we aimed to replicate these findings and provide an alternative explanation based on the list-before-the-last paradigm. We propose that in the forget condition, participants may strategically retrieve List 1 in response to the forget cue, contributing to selective forgetting. Previous research suggests that explicit retrieval of earlier-leaned information causes a contextual shift, resulting in forgetting of target information. Verbal reports from Experiments 1 and 2 indicated that participants often covertly select a retrieval strategy to forget the most recent list. In Experiment 3, explicit instructions to retrieve resulted in significant forgetting. Directly manipulating forgetting strategy between participants in Experiment 4 suggested that retrieval may be one of several effective mechanisms to forget recently-encountered information. In the retrieval conditions, the data support our claim that in the absence of explicit postcue encoding, people can strategically retrieve earlier-learned information to forget. This novel forgetting mechanism is probably also used outside of the laboratory to "roll back" memory for incorrect information. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

An event-related potential study of the testing effect: Electrophysiological evidence for context-dependent processes changing throughout repeated practice.

The testing effect refers to a special form of performance improvement following practice. Specifically, repeated retrieval attempts improve long-term memory. In the present study we examined the underlying mechanisms of the testing effect as a function of time by investigating the electrophysiological correlates of repeated retrieval practice. We additionally investigated the ERP waveforms of the repeated practice phase as a function of the accuracy on the final test in a "difference due to memory" (Dm) analysis. We found a parietally distributed, increased positive amplitude between 500 and 700 ms, and a more positive parietal wave between 700 and 1000 ms in the later relative to the early phases of retrieval practice. We found parietal Dm effects in the same two time windows in the retrieval practice condition with a more positive amplitude predicting retrieval success on the final test. We interpret the earlier waveform as a component associated with episodic recollection and the later ERP as a component related to post-retrieval evaluation processes. Our results demonstrate the important role of these retrieval-related processes in the facilitating effect of retrieval practice on later retrieval, and show that the involvement of these processes changes throughout practice.

The key to superior memory encoding under stress: the relationship between cortisol response and mnemonic discrimination.

Some previous studies have shown that increased stress hormone levels have beneficial effects on memory encoding; however, there is no clear consensus on which encoding-related processes are affected by stress hormones. In the present study, we investigated the relationship between interindividual differences in neuroendocrine response to acute stress and interference resolution (i.e., mnemonic discrimination). Participants were healthy young adults who were exposed to physical and psychological stressors (Socially Evaluated Cold Pressor Test). Then participants completed the modified version of the Mnemonic Similarity Task. Specifically, they were presented with photographs of emotionally arousing (negative and positive) and nonarousing (neutral) scenes followed by a recognition memory test where they saw a mixture of old and new stimuli. Crucially, participants were also presented with critical lure items, that is, visually similar stimuli to ones presented at encoding. We found that participants who had higher cortisol response to the stressors were better in discriminating between the studied items and their visually similar lures. This effect was present for the arousing and nonarousing materials as well. These findings suggest that increased hormonal response to acute stress has a beneficial impact on the formation of distinct, nonoverlapping, unique memory representations, and consequently, on episodic memory encoding processes.

Learning to distinguish: shared perceptual features and discrimination practice tune behavioural pattern separation.

Pattern separation is a computational mechanism performed by the hippocampus allowing the reduction of overlap between sensory inputs with similar perceptual features. Our first aim was to develop a new paradigm sensitive to the behavioural consequences of pattern separation (mnemonic discrimination). For this purpose, we constructed morphed face stimuli with parametrically changing levels of similarity. After encoding participants saw studied items and similar lure faces. Perceptual similarity affected false recognition and there was a gradual reduction in discrimination accuracy with the increment of similarity between the stimuli. However, confidence ratings were sensitive to smaller changes (Experiment 1) than the other test type with "old"/"similar"/"new" response options (Experiment 2). Mnemonic discrimination relies strongly on retrieving details of the original stimulus. Therefore, we investigated whether pattern separation can be tuned by retrieval in the form of a discrimination task (Experiment 3). Our findings suggest that repeatedly encountering the stimuli within a two-alternative forced-choice task (in comparison with the repeated presentation of the material) increased both the correct identification and the false recognition of similar stimuli two days after encoding. We conclude that basic computational mechanisms of the hippocampus can be tuned by a task that requires discrimination between studied and new stimuli.

Irrelevant background context decreases mnemonic discrimination and increases false memory.

One of the greatest commonplaces in memory research is that context improves recall and enhances or leaves recognition intact. Here we present results which draw attention to the fact that the reappearance of irrelevant and unattended background contexts of encoding significantly impairs memory discrimination functions. This manuscript presents the results of two experiments in which participants made indoor/outdoor judgements for a large number of object images presented together with individual, irrelevant and presumably unattended background scenes. On a subsequent unexpected recognition test participants saw the incidentally encoded target objects, visually similar lures or new foil objects on the same or new background scenes. Our results showed that although the reappearance of the background scene raised the hit rate for target objects, it decreased mnemonic discrimination, a behavioral score for pattern separation, a hippocampal function that is affected in early dementia. Furthermore, the presence of the encoded background scene at the recognition test increased the false recognition of lure objects, even when participants were explicitly instructed to neglect the context scene. Altogether these results gave evidence that if context increases recognition hits for target memories, it does so at the cost of increasing false recognition and diminished discriminability for similar information.

Pupil size changes signal hippocampus-related memory functions.

A major task of episodic memory is to create unique, distinguishable representations of highly overlapping perceptual inputs. Several studies on this basic function have shown that it is based on the intact functioning of certain subregions of the hippocampus and is among the most sensitive behavioral indicators of mild cognitive impairment (MCI) and dementia. Here we assessed pupil dilation associated with performance in a widely used recognition paradigm that aims to uncover the intactness of fine-graded mnemonic discrimination. A sample of healthy undergraduate students was used. First, we showed that the correct discrimination between highly similar lure items and target items elicit larger pupil response than correct target identification. Second, we found that mnemonic discrimination is associated with larger pupil response in general as compared to target identification, regardless of whether the response was correct or not. These results suggest the pupil changes differentiate mnemonic discrimination and memory identification processes in recognition performance.

Reversing the testing effect by feedback is a matter of performance criterion at practice.

Retrieval practice is generally considered to be one of the most effective long-term learning strategies and is presumed to be more favorable than repeated study. However, a few recent studies have demonstrated that repetitive feedback at final recall can reverse the long-term advantage of testing over restudy. The result that feedback at long-term tests can dramatically decrease the relative effectiveness of retrieval-based learning could be important for both theoretical and practical reasons. Considering that these earlier studies administered low retrieval success at retrieval practice, we investigated whether the effect of feedback on the testing effect is modulated by the level of retrieval success during practice. In three experiments the level of success at retrieval practice was manipulated by multiple pre-practice learning trials, and multiple tests with feedback were applied after a 1-week retention interval at final recall. Our results have demonstrated that a feedback-induced reversed testing effect was present only at low retrieval success during practice (Experiment 1), whereas with moderate (Experiment 2) and high retrieval success (Experiment 3) during practice a significant testing effect emerged and no reversed testing effect was found even after repeated cycles of feedback. These results point to the conclusion that the level of retrieval success was the key factor in reversing the testing effect in earlier studies. Application of high retrieval success during practice can produce long-lasting accessible memories even in learning settings applying multiple tests with feedback.

Enhanced mnemonic discrimination for emotional memories: the role of arousal in interference resolution.

In the present study we investigated the long-standing question whether and why emotionally arousing memories are more distinct as compared to neutral experiences. We assumed that memory benefits from the distinctiveness of emotional information, and that emotions affect encoding by reducing interference among overlapping memory representations. Since pattern separation is the process which minimizes interference between memory representations with similar features, we examined the behavioral manifestation of putative neural mechanisms enabling pattern separation (i.e. mnemonic discrimination) for emotionally arousing materials using the Mnemonic Similarity Task with negative, positive, and neutral images as stimuli. Immediately after incidental encoding, subjects were presented with stimuli they had seen at encoding and also with new items. Crucially, participants were also presented with lure images that were visually similar to ones they had seen before. Response options were old, new, and similar. Our results showed that individuals were better in discriminating between similar, emotionally arousing memories, when compared to the neutral stimuli. Moreover, this so-called lure discrimination performance was better for the negative images, than it was for the positive stimuli. Finally, we showed that the high arousing negative stimuli were better separated than the low arousing negative stimuli, and a similar pattern of results was found for the positive items. Altogether, these findings suggest that lure discrimination is modulated by arousal and not by valence. We argue that noradrenergic activity might facilitate interference resolution among memory representations with similar features, and that superior pattern separation might play a key role in memory enhancement for emotional experiences.

Behavioural pattern separation is strongly associated with familiarity-based decisions.

Pattern separation is the process that minimises interference between memory representations with similar features and is suggested to be associated with hippocampus-related recollection. We tested this hypothesis using the incidental Mnemonic Similarity Task with old (target), similar (lure), and new (foil) items presented on a recognition test, which is widely used for detecting individual differences in behavioural pattern separation performance. In Experiment 1, participants made old/similar/new decisions and rated decision confidence on a scale ranging from "not at all sure" to "very sure". In Experiment 2, participants made recognition confidence judgments on a scale ranging between "sure it was new" and "sure it was old". In Experiment 3, subjects gave old/similar/new decisions and made a secondary Remember/Know/Guess judgment. In Experiment 1, confidence ratings were higher for targets compared to lures when we analysed correct responses (old for targets and similar for lures). Additionally, we found a symmetrical ROC curve and a linear zROC curve for target-lure discrimination in Experiment 2. Finally, we found a bias toward Know responses when we analysed behavioural pattern separation performance (i.e., the rate of similar responses given to the lures). These findings suggest that familiarity, rather than recollection, contributes to behavioural pattern separation performance.

Retrieval practice decreases processing load of recall: Evidence revealed by pupillometry.

Retrieval practice is an effective long-term learning strategy. Items practiced through repeated retrieval are resistant to interference, stress, and secondary load, which attributes also characterize automatization in skill learning. In two experiments, we investigated whether retrieval practice is associated with decrease in processing load, which is a further attribute of automatization. Participants first learned paired associates, and then they practiced the items either by repeatedly studying or engaging in retrieval practice. Then their memory was assessed after either five minutes (Experiment 1) or one week (Experiment 2). Processing load was measured by assessing task-evoked pupil dilation during both retrieval practice and later recall. The pattern of results was similar in both experiments. During retrieval practice, processing load decreased during consecutive practice cycles. Moreover, during the final recall test, the retrieval of previously retrieval practiced items required less processing resources, as compared to the retrieval of previously restudied items. Our results suggest that repeated retrieval reduces processing load as well as attentional control involvement during practice and later recall.

Impaired sequential and partially compensated probabilistic skill learning in Parkinson's disease.

The striatal dopaminergic dysfunction in Parkinson's disease (PD) has been associated with deficits in skill learning in numerous studies, but some of the findings remain controversial. Our aim was to explore the generality of the learning deficit using two widely reported skill learning tasks in the same group of Parkinson's patients. Thirty-four patients with PD (mean age: 62.83 years, SD: 7.67) were compared to age-matched healthy adults. Two tasks were employed: the Serial Reaction Time Task (SRT), testing the learning of motor sequences, and the Weather Prediction (WP) task, testing non-sequential probabilistic category learning. On the SRT task, patients with PD showed no significant evidence for sequence learning. These results support and also extend previous findings, suggesting that motor skill learning is vulnerable in PD. On the WP task, the PD group showed the same amount of learning as controls, but they exploited qualitatively different strategies in predicting the target categories. While controls typically combined probabilities from multiple predicting cues, patients with PD instead focused on individual cues. We also found moderate to high correlations between the different measures of skill learning. These findings support our hypothesis that skill learning is generally impaired in PD, and can in some cases be compensated by relying on alternative learning strategies.

How the size of the to-be-learned material influences the encoding and later retrieval of associative memories: A pupillometric assessment.

Pupillometry have recently added valuable insights about the cognitive and possible neurobiological processes underlying episodic memory. Most of the studies, however, investigated recognition memory, which only partially relies on cue-driven recollection, the hallmark feature of episodic memory. Here we measured pupil size during a paired associate learning task, where participants encoded word-pairs, and after a short delay they took part in a cued recall. Importantly, we manipulated the size of the learning set: participants either learnt two, four or eight word-pairs in a row. As expected, increasing set size resulted in larger forgetting, assumingly as a consequence of weaker memory strength for the word-pairs. Our results show an important difference between pupil size changes observed during encoding and retrieval. During retrieval, the pupil instantly begun to dilate, as a sign of increased processing load accompanying the retrieval of the target memory. Importantly, large set size was also associated with larger pupil dilation during retrieval. This supports the notion that pupil dilation can be regarded as a marker of memory strength. In contrast, during encoding, pupil dilation decreased with increasing amount of encoded information, which might be due to the overuse of attentional resources. Furthermore, we also found that serial position during encoding modulated subsequent memory effects: for the first three serial positions, successful recall was predicted by larger pupil dilation during encoding, whereas such subsequent memory effect was absent for later serial positions. These results suggest that the amount of information independently modulates pupil dilation during encoding and retrieval, and support the assumption that pupillometric investigation of paired associate learning could be an informative way to investigate the cognitive and neurobiological processes of episodic memory.

Successful list-method directed forgetting without retroactive interference of post-instruction learning.

The focus of the study is the role of interference in list-method directed forgetting. More specifically, our question was whether retroactive interference of the to-be-remembered information is a necessary prerequisite for the directed forgetting effect. In Experiment 1 we used a directed forgetting procedure with one learning list without the interference of any to-be-remembered information. In line with previous results, we did not find a significant directed forgetting effect. Experiment 2 applied a directed forgetting procedure with two study lists, however, the forget instruction was given following the second list. So, List 2 items were designated as to-be-forgotten items, without further learning, whereas List 1 items were to-be-remembered items. The forget instruction selectively decreased the recall of List 2 items, without decreasing the recall performance for List 1. In Experiment 3, using the same procedure with different items, smaller learning lists and reversed output order, we replicated the results of Experiment 2. Altogether, these results point to a flexible, goal-related nature of the directed forgetting phenomenon, showing that some form of interference is a necessary requirement for successful directed forgetting. However, proactive interference of to-be-remembered information in interaction with a forget instruction is suitable for forgetting of subsequently encoded information.

Anodal transcranial direct current stimulation of the right dorsolateral prefrontal cortex impairs long-term retention of reencountered memories.

Repeated encounter with encoded memories is often a fundamental component of long-term learning processes, however, the role of repeated access to encoded memories in long-term consolidation is yet to be clarified. Here we investigated whether the long-term retention of newly acquired associative memories is affected if one of the central areas of the attentional control network is stimulated before or after repeated access to acquired information. Non-clinical participants (undergraduate students, N = 118) were exposed to an associative verbal learning task. Following the initial learning of word pairs, memories for the word pairs were reencountered either by re-presenting the stimuli to the participants for restudying or by cued recall. The reencounter phase was either preceded by (Experiment 1) or followed by (Experiment 2) anodal transcranial Direct Current Stimulation of the right dorsolateral prefrontal cortex. Memory retention was assessed seven days after the reencounter phase. When we measured successful access to learned paired-associates in the reencounter phase, there was no difference between the anodal and sham stimulation condition in either Experiment 1 or 2. However, and importantly, anodal stimulation had a detrimental impact on long-term memory but only when stimulation preceded the reencountering of memories (in Experiment 1). Our results suggest that stimulation of the so-called control network during repeated access to acquired information disrupts the long-term retention of these memories. These findings are in line with earlier results showing that repeated access to learned information systematically decreases the involvement of control processes in retrieval and presumably promotes learning through the automatization of cue-target association. At a neural level, a possible substrate of repeated memory reencountering is a shift in frontohippocampal connectivity.

Physiological Measures of Dopaminergic and Noradrenergic Activity During Attentional Set Shifting and Reversal.

Dopamine (DA) and noradrenaline (NA) are important neurotransmitters, which are suggested to play a vital role in modulating the neural circuitry involved in the executive control of cognition. One way to investigate the functions of these neurotransmitter systems is to assess physiological indices of DA and NA transmission. Here we examined how variations of spontaneous eye-blink rate and pupil size, as indirect measures of DA and NA activity, respectively, are related to performance in a hallmark aspect of executive control: attentional set shifting. We used the Intra/Extradimensional Set Shifting Task, where participants have to choose between different compound stimuli while the stimulus-reward contingencies change periodically. During such rule shifts, participants have to refresh their attentional set while they reassess which stimulus-features are relevant. We found that both eye-blink rate (EBR) and pupil size increased after rule shifts, when explorative processes are required to establish stimulus-reward contingencies. Furthermore, baseline pupil size was related to performance during the most difficult, extradimensional set shifting stage, whereas baseline EBR was associated with task performance prior to this stage. Our results support a range of neurobiological models suggesting that the activity of DA and NA neurotransmitter systems determines individual differences in executive functions (EF), possibly by regulating neurotransmission in prefrontal circuits. We also suggest that assessing specific, easily accessible indirect physiological markers, such as pupil size and blink rate, contributes to the comprehension of the relationship between neurotransmitter systems and EF.