Memory reactivation in slow wave sleep enhances relational learning in humans.

Sleep boosts the integration of memories, and can thus facilitate relational learning. This benefit may be due to memory reactivation during non-REM sleep. We set out to test this by explicitly cueing reactivation using a technique called targeted memory reactivation (TMR), in which sounds are paired with learned material in wake and then softly played during subsequent sleep, triggering reactivation of the associated memories. We specifically tested whether TMR in slow wave sleep leads to enhancements in inferential thinking in a transitive inference task. Because the Up-phase of the slow oscillation is more responsive to cues than the Down-phase, we also asked whether Up-phase stimulation is more beneficial for such integration. Our data show that TMR during the Up-Phase boosts the ability to make inferences, but only for the most distant inferential leaps. Up-phase stimulation was also associated with detectable memory reinstatement, whereas Down-phase stimulation led to below-chance performance the next morning. Detection of memory reinstatement after Up-state stimulation was negatively correlated with performance on the most difficult inferences the next morning. These findings demonstrate that cueing memory reactivation at specific time points in sleep can benefit difficult relational learning problems.

Effects of Targeted Memory Reactivation on Cortical Networks.

Sleep is a complex physiological process with an important role in memory consolidation characterised by a series of spatiotemporal changes in brain activity and connectivity. Here, we investigate how task-related responses differ between pre-sleep wake, sleep, and post-sleep wake. To this end, we trained participants on a serial reaction time task using both right and left hands using Targeted Memory Reactivation (TMR), in which auditory cues are associated with learned material and then re-presented in subsequent wake or sleep periods in order to elicit memory reactivation. The neural responses just after each cue showed increased theta band connectivity between frontal and other cortical regions, as well as between hemispheres, in slow wave sleep compared to pre- or post-sleep wake. This pattern was consistent across the cues associated with both right- and left-handed movements. We also searched for hand-specific connectivity and found that this could be identified in within-hemisphere connectivity after TMR cues during sleep and post-sleep sessions. The fact that we could identify which hand had been cued during sleep suggests that these connectivity measures could potentially be used to determine how successfully memory is reactivated by our manipulation. Collectively, these findings indicate that TMR modulates the brain cortical networks showing clear differences between wake and sleep connectivity patterns.

Sleep-related benefits to transitive inference are modulated by encoding strength and joint rank.

Transitive inference is a measure of relational learning that has been shown to improve across sleep. Here, we examine this phenomenon further by studying the impact of encoding strength and joint rank. In experiment 1, participants learned adjacent premise pairs and were then tested on inferential problems derived from those pairs. In line with prior work, we found improved transitive inference performance after retention across a night of sleep compared with wake alone. Experiment 2 extended these findings using a within-subject design and found superior transitive inference performance on a hierarchy, consolidated across 27 h including sleep compared with just 3 h of wake. In both experiments, consolidation-related improvement was enhanced when presleep learning (i.e., encoding strength) was stronger. We also explored the interaction of these effects with the joint rank effect, in which items were scored according to their rank in the hierarchy, with more dominant item pairs having the lowest scores. Interestingly, the consolidation-related benefit was greatest for more dominant inference pairs (i.e., those with low joint rank scores). Overall, our findings provide further support for the improvement of transitive inference across a consolidation period that includes sleep. We additionally show that encoding strength and joint rank strongly modulate this effect.

Rule Abstraction Is Facilitated by Auditory Cuing in REM Sleep.

Sleep facilitates abstraction, but the exact mechanisms underpinning this are unknown. Here, we aimed to determine whether triggering reactivation in sleep could facilitate this process. We paired abstraction problems with sounds, then replayed these during either slow-wave sleep (SWS) or rapid eye movement (REM) sleep to trigger memory reactivation in 27 human participants (19 female). This revealed performance improvements on abstraction problems that were cued in REM, but not problems cued in SWS. Interestingly, the cue-related improvement was not significant until a follow-up retest 1 week after the manipulation, suggesting that REM may initiate a sequence of plasticity events that requires more time to be implemented. Furthermore, memory-linked trigger sounds evoked distinct neural responses in REM, but not SWS. Overall, our findings suggest that targeted memory reactivation in REM can facilitate visual rule abstraction, although this effect takes time to unfold.SIGNIFICANCE STATEMENT The ability to abstract rules from a corpus of experiences is a building block of human reasoning. Sleep is known to facilitate rule abstraction, but it remains unclear whether we can manipulate this process actively and which stage of sleep is most important. Targeted memory reactivation (TMR) is a technique that uses re-exposure to learning-related sensory cues during sleep to enhance memory consolidation. Here, we show that TMR, when applied during REM sleep, can facilitate the complex recombining of information needed for rule abstraction. Furthermore, we show that this qualitative REM-related benefit emerges over the course of a week after learning, suggesting that memory integration may require a slower form of plasticity.

Towards a Personalized Multi-Domain Digital Neurophenotyping Model for the Detection and Treatment of Mood Trajectories.

The commercial availability of many real-life smart sensors, wearables, and mobile apps provides a valuable source of information about a wide range of human behavioral, physiological, and social markers that can be used to infer the user's mental state and mood. However, there are currently no commercial digital products that integrate these psychosocial metrics with the real-time measurement of neural activity. In particular, electroencephalography (EEG) is a well-validated and highly sensitive neuroimaging method that yields robust markers of mood and affective processing, and has been widely used in mental health research for decades. The integration of wearable neuro-sensors into existing multimodal sensor arrays could hold great promise for deep digital neurophenotyping in the detection and personalized treatment of mood disorders. In this paper, we propose a multi-domain digital neurophenotyping model based on the socioecological model of health. The proposed model presents a holistic approach to digital mental health, leveraging recent neuroscientific advances, and could deliver highly personalized diagnoses and treatments. The technological and ethical challenges of this model are discussed.

Emotional valence modulates the topology of the parent-infant inter-brain network.

Emotional communication between parents and children is crucial during early life, yet little is known about its neural underpinnings. Here, we adopt a dual connectivity approach to assess how positive and negative emotions modulate the interpersonal neural network between infants and their mothers during naturalistic interaction. Fifteen mothers were asked to model positive and negative emotions toward pairs of objects during social interaction with their infants (mean age 10.3 months) whilst the neural activity of both mothers and infants was concurrently measured using dual electroencephalography (EEG). Intra-brain and inter-brain network connectivity in the 6-9 Hz range (i.e. infant Alpha band) during maternal expression of positive and negative emotions was computed using directed (partial directed coherence, PDC) and non-directed (phase-locking value, PLV) connectivity metrics. Graph theoretical measures were used to quantify differences in network topology as a function of emotional valence. We found that inter-brain network indices (Density, Strength and Divisibility) consistently revealed strong effects of emotional valence on the parent-child neural network. Parents and children showed stronger integration of their neural processes during maternal demonstrations of positive than negative emotions. Further, directed inter-brain metrics (PDC) indicated that mother to infant directional influences were stronger during the expression of positive than negative emotional states. These results suggest that the parent-infant inter-brain network is modulated by the emotional quality and tone of dyadic social interactions, and that inter-brain graph metrics may be successfully applied to examine these changes in parent-infant inter-brain network topology.

Towards broadening Forensic DNA Phenotyping beyond pigmentation: Improving the prediction of head hair shape from DNA.

Human head hair shape, commonly classified as straight, wavy, curly or frizzy, is an attractive target for Forensic DNA Phenotyping and other applications of human appearance prediction from DNA such as in paleogenetics. The genetic knowledge underlying head hair shape variation was recently improved by the outcome of a series of genome-wide association and replication studies in a total of 26,964 subjects, highlighting 12 loci of which 8 were novel and introducing a prediction model for Europeans based on 14 SNPs. In the present study, we evaluated the capacity of DNA-based head hair shape prediction by investigating an extended set of candidate SNP predictors and by using an independent set of samples for model validation. Prediction model building was carried out in 9674 subjects (6068 from Europe, 2899 from Asia and 707 of admixed European and Asian ancestries), used previously, by considering a novel list of 90 candidate SNPs. For model validation, genotype and phenotype data were newly collected in 2415 independent subjects (2138 Europeans and 277 non-Europeans) by applying two targeted massively parallel sequencing platforms, Ion Torrent PGM and MiSeq, or the MassARRAY platform. A binomial model was developed to predict straight vs. non-straight hair based on 32 SNPs from 26 genetic loci we identified as significantly contributing to the model. This model achieved prediction accuracies, expressed as AUC, of 0.664 in Europeans and 0.789 in non-Europeans; the statistically significant difference was explained mostly by the effect of one EDAR SNP in non-Europeans. Considering sex and age, in addition to the SNPs, slightly and insignificantly increased the prediction accuracies (AUC of 0.680 and 0.800, respectively). Based on the sample size and candidate DNA markers investigated, this study provides the most robust, validated, and accurate statistical prediction models and SNP predictor marker sets currently available for predicting head hair shape from DNA, providing the next step towards broadening Forensic DNA Phenotyping beyond pigmentation traits.

Using brain connectivity metrics from synchrostates to perform motor imagery classification in EEG-based BCI systems.

Phase synchronisation between different neural groups is considered an important source of information to understand the underlying mechanisms of brain cognition. This Letter investigated phase-synchronisation patterns from electroencephalogram (EEG) signals recorded from ten healthy participants performing motor imagery (MI) tasks using schematic emotional faces as stimuli. These phase-synchronised states, named synchrostates, are specific for each cognitive task performed by the user. The maximum and minimum number of occurrence states were selected for each subject and task to extract the connectivity network measures based on graph theory to feed a set of classification algorithms. Two MI tasks were successfully classified with the highest accuracy of 85% with corresponding sensitivity and specificity of 85%. In this work, not only the performance of different supervised learning techniques was studied, as well as the optimal subset of features to obtain the best discrimination rates. The robustness of this classification method for MI tasks indicates the possibility of expanding its use for online classification of the brain-computer interface (BCI) systems.

Tracking age-correlated DNA methylation markers in the young.

DNA methylation is the most extensively studied epigenetic signature, with a large number of studies reporting age-correlated CpG sites in overlapping genes. However, most of these studies lack sample coverage of individuals under 18 years old and therefore little is known about the progression of DNA methylation patterns in children and adolescents. In the present study we aimed to select candidate age-correlated DNA methylation markers based on public datasets from Illumina BeadChip arrays and previous publications, then to explore the resulting markers in 209 blood samples from donors aged between 2 to 18 years old using the EpiTYPER® DNA methylation analysis system. Results from our analyses identified six genes highly correlated with age in the young, in particular the gene KCNAB3, which indicates its potential as a highly informative and specific age biomarker for childhood and adolescence. We outline a preliminary age prediction model based on quantile regression that uses data from the six CpG sites most strongly correlated with age ranges extended to include children and adolescents.

Identification of memory reactivation during sleep by EEG classification.

Memory reactivation during sleep is critical for consolidation, but also extremely difficult to measure as it is subtle, distributed and temporally unpredictable. This article reports a novel method for detecting such reactivation in standard sleep recordings. During learning, participants produced a complex sequence of finger presses, with each finger cued by a distinct audio-visual stimulus. Auditory cues were then re-played during subsequent sleep to trigger neural reactivation through a method known as targeted memory reactivation (TMR). Next, we used electroencephalography data from the learning session to train a machine learning classifier, and then applied this classifier to sleep data to determine how successfully each tone had elicited memory reactivation. Neural reactivation was classified above chance in all participants when TMR was applied in SWS, and in 5 of the 14 participants to whom TMR was applied in N2. Classification success reduced across numerous repetitions of the tone cue, suggesting either a gradually reducing responsiveness to such cues or a plasticity-related change in the neural signature as a result of cueing. We believe this method will be valuable for future investigations of memory consolidation.