Visual Exploration at Higher Fixation Frequency Increases Subsequent Memory Recall.

Only a small proportion of what we see can later be recalled. Up to date it is unknown how far differences in visual exploration during encoding affect the strength of episodic memories. Here, we identified individual gaze characteristics by analyzing eye tracking data in a picture encoding task performed by 967 healthy subjects during fMRI. We found a positive correlation between fixation frequency during visual exploration and subsequent free recall performance. Brain imaging results showed a positive correlation of fixation frequency with activations in regions related to vision and memory, including the medial temporal lobe. To investigate if higher fixation frequency is causally linked to better memory, we experimentally manipulated visual exploration patterns in an independent population of 64 subjects. Doubling the number of fixations within a given exploration time increased subsequent free recall performance by 19%. Our findings provide evidence for a causal relationship between fixation frequency and episodic memory for visual information.

Traditional and Digital Biomarkers: Two Worlds Apart?

The identification and application of biomarkers in the clinical and medical fields has an enormous impact on society. The increase of digital devices and the rise in popularity of health-related mobile apps has produced a new trove of biomarkers in large, diverse, and complex data. However, the unclear definition of digital biomarkers, population groups, and their intersection with traditional biomarkers hinders their discovery and validation. We have identified current issues in the field of digital biomarkers and put forth suggestions to address them during the DayOne Workshop with participants from academia and industry. We have found similarities and differences between traditional and digital biomarkers in order to synchronize semantics, define unique features, review current regulatory procedures, and describe novel applications that enable precision medicine.

Resting-state functional connectivity remains unaffected by preceding exposure to aversive visual stimuli.

While much is known about immediate brain activity changes induced by the confrontation with emotional stimuli, the subsequent temporal unfolding of emotions has yet to be explored. To investigate whether exposure to emotionally aversive pictures affects subsequent resting-state networks differently from exposure to neutral pictures, a resting-state fMRI study implementing a two-group repeated-measures design in healthy young adults (N = 34) was conducted. We focused on investigating (i) patterns of amygdala whole-brain and hippocampus connectivity in both a seed-to-voxel and seed-to-seed approach, (ii) whole-brain resting-state networks with an independent component analysis coupled with dual regression, and (iii) the amygdala's fractional amplitude of low frequency fluctuations, all while EEG recording potential fluctuations in vigilance. In spite of the successful emotion induction, as demonstrated by stimuli rating and a memory-facilitating effect of negative emotionality, none of the resting-state measures was differentially affected by picture valence. In conclusion, resting-state networks connectivity as well as the amygdala's low frequency oscillations appear to be unaffected by preceding exposure to widely used emotionally aversive visual stimuli in healthy young adults.

Picture free recall performance linked to the brain's structural connectome.

INTRODUCTION: Memory functions are highly variable between healthy humans. The neural correlates of this variability remain largely unknown. METHODS: Here, we investigated how differences in free recall performance are associated with DTI-based properties of the brain's structural connectome and with grey matter volumes in 664 healthy young individuals tested in the same MR scanner. RESULTS: Global structural connectivity, but not overall or regional grey matter volumes, positively correlated with recall performance. Moreover, a set of 22 inter-regional connections, including some with no previously reported relation to human memory, such as the connection between the temporal pole and the nucleus accumbens, explained 7.8% of phenotypic variance. CONCLUSIONS: In conclusion, this large-scale study indicates that individual memory performance is associated with the level of structural brain connectivity.

A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory.

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10-8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.

The NCAM1 gene set is linked to depressive symptoms and their brain structural correlates in healthy individuals.

Depressive symptoms exist on a continuum, the far end of which is found in depressive disorders. Utilizing the continuous spectrum of depressive symptoms may therefore contribute to the understanding of the biological underpinnings of depression. Gene set enrichment analysis (GSEA) is an important tool for the identification of gene groups linked to complex traits, and was applied in the present study on genome-wide association study (GWAS) data of depression scores and their brain-level structural correlates in healthy young individuals. On symptom level (i.e. depression scores), robust enrichment was identified for two gene sets: NCAM1 Interactions and Collagen Formation. Depression scores were also associated with decreased fractional anisotropy (FA) - a brain white matter property - within the forceps minor and the left superior temporal longitudinal fasciculus. Within each of these tracts, mean FA value of depression score-associated voxels was used as a phenotype in a subsequent GSEA. The NCAM1 Interactions gene set was significantly enriched in these tracts. By linking the NCAM1 Interactions gene set to depression scores and their structural brain correlates in healthy participants, the current study contributes to the understanding of the molecular underpinnings of depressive symptomatology.

Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease.

IMPORTANCE: Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. OBJECTIVE: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. MAIN OUTCOMES AND MEASURES: Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.

Computational dissection of human episodic memory reveals mental process-specific genetic profiles.

Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition-based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory.

Sex-dependent dissociation between emotional appraisal and memory: a large-scale behavioral and fMRI study.

Extensive evidence indicates that women outperform men in episodic memory tasks. Furthermore, women are known to evaluate emotional stimuli as more arousing than men. Because emotional arousal typically increases episodic memory formation, the females' memory advantage might be more pronounced for emotionally arousing information than for neutral information. Here, we report behavioral data from 3398 subjects, who performed picture rating and memory tasks, and corresponding fMRI data from up to 696 subjects. We were interested in the interaction between sex and valence category on emotional appraisal, memory performances, and fMRI activity. The behavioral results showed that females evaluate in particular negative (p < 10(-16)) and positive (p = 2 × 10(-4)), but not neutral pictures, as emotionally more arousing (pinteraction < 10(-16)) than males. However, in the free recall females outperformed males not only in positive (p < 10(-16)) and negative (p < 5 × 10(-5)), but also in neutral picture recall (p < 3.4 × 10(-8)), with a particular advantage for positive pictures (pinteraction < 4.4 × 10(-10)). Importantly, females' memory advantage during free recall was absent in a recognition setting. We identified activation differences in fMRI, which corresponded to the females' stronger appraisal of especially negative pictures, but no activation differences that reflected the interaction effect in the free recall memory task. In conclusion, females' valence-category-specific memory advantage is only observed in a free recall, but not a recognition setting and does not depend on females' higher emotional appraisal.

Dynamic modulation of amygdala-hippocampal connectivity by emotional arousal.

Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence.

Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity.

Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143). The voltage-gated cation channel activity gene set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene set also to working memory-related activity in the parietal cortex and the cerebellum. Gene set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity, and psychopathology.

BAIAP2 is related to emotional modulation of human memory strength.

Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings. Here we combined a computational model-based analysis of memory-related processes with high density genetic information derived from a genome-wide study in healthy young adults. After identifying the best-fitting model for a verbal memory task and estimating the best-fitting individual cognitive parameters, we found a common variant in the gene encoding the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) that was related to the model parameter reflecting modulation of verbal memory strength by negative valence. We also observed an association between the same genetic variant and a similar emotional modulation phenotype in a different population performing a picture memory task. Furthermore, using functional neuroimaging we found robust genotype-dependent differences in activity of the parahippocampal cortex that were specifically related to successful memory encoding of negative versus neutral information. Finally, we analyzed cortical gene expression data of 193 deceased subjects and detected significant BAIAP2 genotype-dependent differences in BAIAP2 mRNA levels. Our findings suggest that model-based dissociation of specific cognitive parameters can improve the understanding of genetic underpinnings of human learning and memory.

Human genome-guided identification of memory-modulating drugs.

In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory--a trait central to posttraumatic stress disorder--and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand-receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.

Computerised working memory training in healthy adults: a comparison of two different training schedules.

This study compared a high intensity working memory training (45 minutes, 4 times per week for 4 weeks) with a distributed training (45 minutes, 2 times per week for 8 weeks) in middle-aged, healthy adults. The aim was to clarify whether a computerised working memory training is effective and whether intensity of training influences training outcome. To evaluate the efficacy and possible transfer effects, a neuropsychological test battery assessing short- and long-term memory, working memory, executive functions and mental speed was applied at baseline and at retest. Our results indicate that the distributed training led to increased performance in all cognitive domains when compared to the high intensity training and the control group without training. The most significant differences revealed by interaction contrasts were found for verbal and visual working memory, verbal short-term memory and mental speed. These results support the hypothesis that cognitive enhancement by cognitive intervention is effective in healthy individuals, and that a distributed training schedule is superior to a high intensity intervention.

PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

A role for α-adducin (ADD-1) in nematode and human memory.

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that α-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for α-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases.

Testosterone levels in healthy men are related to amygdala reactivity and memory performance.

Testosterone is a steroid hormone thought to influence both emotional and cognitive functions. It is unknown, however, if testosterone also affects the interaction between these two domains, such as the emotional arousal-induced enhancement of memory. Healthy subjects (N=234) encoded pictures taken from the International Affective Picture System (IAPS) during functional magnetic resonance imaging (fMRI) and underwent a free recall test 10 min after memory encoding. We show that higher endogenous testosterone levels at encoding were associated with higher arousal ratings of neutral pictures in men. fMRI analysis revealed that higher testosterone levels were related to increased brain activation in the amygdala during encoding of neutral pictures. Moreover, endogenous testosterone levels were positively correlated with the number of freely recalled neutral pictures. No such relations were found in women. These findings point to a male-specific role for testosterone in enhancing memory by increasing the biological salience of incoming information.

Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory.

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed "missing heritability." The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (P(nominal combined)=0.000001). The epistatic interaction was robust, as it was significant in a screening (P(nominal)=0.0000012) and in a replication sample (P(nominal)=0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (P(nominal)=0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits.

Microarray-based maps of copy-number variant regions in European and sub-Saharan populations.

The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies. Here we provide a cross-population, microarray-based map of copy-number variant regions (CNVRs) to enable reliable interpretation of CNV association findings. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to scan the genomes of 1167 individuals from two ethnically distinct populations (Europe, N=717; Rwanda, N=450). Three different CNV-finding algorithms were tested and compared for sensitivity, specificity, and feasibility. Two algorithms were subsequently used to construct CNVR maps, which were also validated by processing subsamples with additional microarray platforms (Illumina 1M-Duo BeadChip, Nimblegen 385K aCGH array) and by comparing our data with publicly available information. Both algorithms detected a total of 42669 CNVs, 74% of which clustered in 385 CNVRs of a cross-population map. These CNVRs overlap with 862 annotated genes and account for approximately 3.3% of the haploid human genome.We created comprehensive cross-populational CNVR-maps. They represent an extendable framework that can leverage the detection of common CNVs and additionally assist in interpreting CNV-based association studies.