Developmental changes in retention and generalization of nonadjacent dependencies over a period containing sleep in 18-mo-old infants.

Sleep promotes the stabilization of memories in adulthood, with a growing literature on the benefits of sleep for memory in infants and children. In two studies, we examined the role of sleep in the retention and generalization of nonadjacent dependencies (NADs; e.g., a-X-b/c-X-d phrases) in an artificial language. Previously, a study demonstrated that over a delay of 4 h, 15 mo olds who nap after training retain a general memory of the NAD rule instead of memory for specific NADs heard during training. In experiment 1, we designed a replication of the nap condition used in the earlier study but tested 18-mo-old infants. Infants of this age retained veridical memory for specific NADs over a delay containing sleep, providing preliminary evidence of the development of memory processes (experiment 1). In experiment 2, we tested 18 mo olds' ability to generalize the NAD to new vocabulary, finding only infants who napped after training generalized their knowledge of the pattern to completely novel phrases. Overall, by 18 mo of age, children retain specific memories over a period containing sleep, and sleep promotes abstract memories to a greater extent than wakefulness.

Technical Validation and Utility of an HLA Class II Tetramer Assay for Type 1 Diabetes: A Multicenter Study.

CONTEXT: Validated assays to measure autoantigen-specific T-cell frequency and phenotypes are needed for assessing the risk of developing diabetes, monitoring disease progression, evaluating responses to treatment, and personalizing antigen-based therapies. OBJECTIVE: Toward this end, we performed a technical validation of a tetramer assay for HLA-DRA-DRB1*04:01, a class II allele that is strongly associated with susceptibility to type 1 diabetes (T1D). METHODS: HLA-DRA-DRB1*04:01-restricted T cells specific for immunodominant epitopes from islet cell antigens GAD65, IGRP, preproinsulin, and ZnT8, and a reference influenza epitope, were enumerated and phenotyped in a single staining tube with a tetramer assay. Single and multicenter testing was performed, using a clone-spiked specimen and replicate samples from T1D patients, with a target coefficient of variation (CV) less than 30%. The same assay was applied to an exploratory cross-sectional sample set with 24 T1D patients to evaluate the utility of the assay. RESULTS: Influenza-specific T-cell measurements had mean CVs of 6% for the clone-spiked specimen and 11% for T1D samples in single-center testing, and 20% and 31%, respectively, for multicenter testing. Islet-specific T-cell measurements in these same samples had mean CVs of 14% and 23% for single-center and 23% and 41% for multicenter testing. The cross-sectional study identified relationships between T-cell frequencies and phenotype and disease duration, sex, and autoantibodies. A large fraction of the islet-specific T cells exhibited a naive phenotype. CONCLUSION: Our results demonstrate that the assay is reproducible and useful to characterize islet-specific T cells and identify correlations between T-cell measures and clinical traits.

Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals.

Class II tetramer reagents for eleven common DR alleles and a DP allele prevalent in the world population were used to identify SARS-CoV-2 CD4+ T cell epitopes. A total of 112, 28 and 42 epitopes specific for Spike, Membrane and Nucleocapsid, respectively, with defined HLA-restriction were identified. Direct ex vivo staining of PBMC with tetramer reagents was used to define immunodominant and subdominant T cell epitopes and estimate the frequencies of these T cells in SARS-CoV-2 exposed and naïve individuals. Majority of SARS-CoV-2 epitopes identified have <67% amino acid sequence identity with endemic coronaviruses and are unlikely to elicit high avidity cross-reactive T cell responses. Four SARS-CoV-2 Spike reactive epitopes, including a DPB1*04:01 restricted epitope, with ≥67% amino acid sequence identity to endemic coronavirus were identified. SARS-CoV-2 T cell lines for three of these epitopes elicited cross-reactive T cell responses to endemic cold viruses. An endemic coronavirus Spike T cell line showed cross-reactivity to the fourth SARS-CoV-2 epitope. Three of the Spike cross-reactive epitopes were subdominant epitopes, while the DPB1*04:01 restricted epitope was a dominant epitope. Frequency analyses showed Spike cross-reactive T cells as detected by tetramers were present at relatively low frequency in unexposed people and only contributed a small proportion of the overall Spike-specific CD4+ T cells in COVID-19 convalescent individuals. In total, these results suggested a very limited number of SARS-CoV-2 T cells as detected by tetramers are capable of recognizing ccCoV with relative high avidity and vice versa. The potentially supportive role of these high avidity cross-reactive T cells in protective immunity against SARS-CoV-2 needs further studies.

The Role of Sleep in Retention of New Words in Habitually and Non-Habitually Napping Children.

Daytime napping contributes to retention of new word learning in children. Importantly, children transition out of regular napping between ages 3-5 years, and the impact of this transition on memory is unclear. Here, we examined the performance of both non-habitually napping children (nap 0-3 days per week, n = 28) and habitually napping children (nap 4-7 days per week, n = 30) on a word learning task after a delay including either sleep or wakefulness. Children ages 3.5-4.5 years old experienced a brief exposure to two novel labels and their referents during training, a scenario that replicates learning experiences children encounter every day. After a 4-h delay, children were tested on the object-label associations. Using mixed effects logistic regression, we compared retention performance. Non-habitual nappers and habitual nappers displayed a different pattern of retention such that non-habitually napping children did equally well on a test of retention regardless of whether they napped or stayed awake during the delay. In contrast, habitually napping children needed a nap after learning to retain the novel object-label associations 4 h later. As a group, habitual nappers who remained awake after learning performed no better than chance on the retention test. As children transition out of naps, they may be less susceptible to interference and are better able to retain newly learned words across a delay including wakefulness.

The Role of Spontaneous Repetitions During Treatment of Morphosyntactic Forms for Children With Developmental Language Disorder.

Purpose Children with developmental language disorder sometimes spontaneously repeat clinician models of morphemes targeted for treatment. We examine how spontaneous repeating of clinician models in the form of recasts associates with improved child production of those emerging morphemes. Method Forty-seven preschool children with developmental language disorder participated in Enhanced Conversational Recast therapy and were monitored for spontaneous repetitions of morphemes modeled by the clinician through conversational recasting. We calculated proportion of correct and incorrect productions elicited during treatment and for generalization probes as well as treatment effect sizes. We then used odds ratios to determine the probability that a spontaneous repetition may precede treatment gains and calculated correlations of correct repetitions with correct in-treatment productions of targets and treatment effect sizes. Results Spontaneous repetitions were highly likely to happen just prior to meaningful treatment progress. Children with higher frequencies of correct spontaneous repetitions of morpheme targets also showed higher frequencies of correct productions of these forms during the course of treatment. Furthermore, children with an earlier onset of repetitions and higher frequencies of correct repetitions showed overall larger effect sizes at the end of treatment. Conclusions Children's use of correct forms in their repetitions may serve as a self-scaffold for mastering productions of the correct form via structural priming mechanisms. Tracking spontaneously repeated targets may be a useful milestone for identifying response to treatment.

A Mediation Appraisal of Catastrophizing, Pain-Related Outcomes, and Race in Adults With Knee Osteoarthritis.

The current cross-sectional study investigates whether pain catastrophizing mediates the relationship between ethnicity/race and pain, disability and physical function in individuals with knee osteoarthritis. Furthermore, this study examined mediation at 2-year follow-up. Participants included 187 community-dwelling adults with unilateral or bilateral knee pain who screened positive for knee osteoarthritis. Participants completed several self-reported pain-related measures and pain catastrophizing subscale at baseline and 2-year follow-up. Non-Hispanic Black (NHB) adults reported greater pain, disability, and poorer functional performance compared to their non-Hispanic White (NHW) counterparts (Ps < .05). NHB adults also reported greater catastrophizing compared to NHW adults. Mediation analyses revealed that catastrophizing mediated the relationship between ethnicity/race and pain outcome measures. Specifically, NHB individuals reported significantly greater pain and disability, and exhibited lower levels of physical function, compared to NHW individuals, and these differences were mediated by higher levels of catastrophizing among NHB persons. Catastrophizing was a significant predictor of pain and disability 2-years later in both ethnic/race groups. These results suggest that pain catastrophizing is an important variable to consider in efforts to reduce ethnic/race group disparities in chronic pain. The findings are discussed in light of structural/systemic factors that may contribute to greater self-reports of pain catastrophizing among NHB individuals. PERSPECTIVE: The current study examines whether pain catastrophizing mediates the relationship between ethnicity/race and OA-related pain, disability, and functional impairment at baseline and during a 2-year follow-up period in non-Hispanic Black and non-Hispanic White adults with knee pain. These results point to the need for interventions that target pain catastrophizing.

A daytime nap combined with nighttime sleep promotes learning in toddlers.

Napping after learning promotes consolidation of new information during infancy. Yet, whether naps play a similar role during toddlerhood, a stage when many children are beginning to transition away from napping, is less clear. In Experiment 1, we examined whether napping after learning promotes generalization of novel category exemplars 24 h later. Young children (N = 54, age range = 29-36 months) viewed three category exemplars in different contexts from each of three categories and remained awake (No-Nap condition) or napped (Nap condition) after encoding and were then tested 24 h later. Children who napped after learning showed superior generalization 24 h later relative to children who did not nap. In a Nap-Control condition tested 4 h after awakening from a nap, children performed at the same low level as in the No-Nap condition, indicating that generalization stemmed from an additional period of nighttime sleep and not simply from a nap or increased time. In Experiment 2, we examined whether nighttime sleep is sufficient for generalization if it occurs soon after learning. An additional group of children (N = 18) learned before bedtime and were tested 4 h after waking up the next day. Children did not generalize as well as those who had a nap combined with subsequent nighttime sleep. These findings suggest that naps, when combined with a period of nighttime sleep, might help toddlers to retain newly learned information and lead to delayed benefits in generalization.

Exploring the "anchor word" effect in infants: Segmentation and categorisation of speech with and without high frequency words.

High frequency words play a key role in language acquisition, with recent work suggesting they may serve both speech segmentation and lexical categorisation. However, it is not yet known whether infants can detect novel high frequency words in continuous speech, nor whether they can use them to help learning for segmentation and categorisation at the same time. For instance, when hearing "you eat the biscuit", can children use the high-frequency words "you" and "the" to segment out "eat" and "biscuit", and determine their respective lexical categories? We tested this in two experiments. In Experiment 1, we familiarised 12-month-old infants with continuous artificial speech comprising repetitions of target words, which were preceded by high-frequency marker words that distinguished the targets into two distributional categories. In Experiment 2, we repeated the task using the same language but with additional phonological cues to word and category structure. In both studies, we measured learning with head-turn preference tests of segmentation and categorisation, and compared performance against a control group that heard the artificial speech without the marker words (i.e., just the targets). There was no evidence that high frequency words helped either speech segmentation or grammatical categorisation. However, segmentation was seen to improve when the distributional information was supplemented with phonological cues (Experiment 2). In both experiments, exploratory analysis indicated that infants' looking behaviour was related to their linguistic maturity (indexed by infants' vocabulary scores) with infants with high versus low vocabulary scores displaying novelty and familiarity preferences, respectively. We propose that high-frequency words must reach a critical threshold of familiarity before they can be of significant benefit to learning.

Parameters of Memory Reconsolidation: Learning Mode Influences Likelihood of Memory Modification.

When previously consolidated hippocampally dependent memory traces are reactivated they enter a vulnerable state in which they can be altered with new information, after which they must be re-consolidated in order to restabilize the trace. The existing body of literature on episodic reconsolidation largely focuses on the when and how of successful memory reactivation. What remains poorly understood is how the nature of newly presented information affects the likelihood of a vulnerable episodic memory being altered. We used our episodic memory reconsolidation paradigm to investigate if the intention to encode impacts what subsequently becomes attributed to an older, reactivated memory. Participants learned two lists of objects separated by 48 h. We integrated a modified item-list directed-forgetting paradigm into the encoding of the second object list by cueing participants to learn some of the objects intentionally (intentional learning), while other objects were presented without a cue (incidental learning). Under conditions of memory reactivation, subjects showed equal rates of memory modification for intentionally- and incidentally-learned objects. However, in the absence of reactivation we observed high misattribution rates of incidentally-learned objects. We consider two interpretations of these data, with contrasting implications for understanding the conditions that influence memory malleability, and suggest further work that should help decide between them.

Associations between sleep and episodic memory updating.

Prior research shows that contextual reminders can reactivate hippocampal links to previously consolidated memories, rendering them susceptible to being updated with new information which then is reconsolidated. Studies implicate sleep in the reconsolidation of reactivated memories, but it is unknown what role sleep plays in updating of a previously consolidated trace with new information. We tracked participants' sleep during an episodic reconsolidation paradigm, first with actigraphy (Experiment 1) then with polysomnography (Experiment 2). Our paradigm involved two learning sessions and a retrieval session, each separated by 48 hr. We reminded participants of the first learning experience immediately prior to the second, which led them to update the earlier memory with elements of the later experience. In Experiment 1, less sleep after Session 1 and more sleep after Session 2 are associated with increased updating. In Experiment 2, N2 sleep spindles (SSs) after the reminder and new learning are associated with more updating, but primarily when spindle activity after Session 1 is low. Thus, total sleep time and N2 SSs contribute to sleep-dependent updating of episodic memory. This outcome is consistent with other work connecting SS activity to the integration of novel information into existing knowledge structures, extended here with the study of how variations in sleep over successive nights contribute to this process. We discuss some possible roles of spindles in the decontextualization of hippocampal memory over time. Although much work addresses the role of sleep in the consolidation of new memories, this work uniquely addresses the contribution of sleep to the updating of a previously consolidated trace with new information.

REM sleep in naps differentially relates to memory consolidation in typical preschoolers and children with Down syndrome.

Sleep is recognized as a physiological state associated with learning, with studies showing that knowledge acquisition improves with naps. Little work has examined sleep-dependent learning in people with developmental disorders, for whom sleep quality is often impaired. We examined the effect of natural, in-home naps on word learning in typical young children and children with Down syndrome (DS). Despite similar immediate memory retention, naps benefitted memory performance in typical children but hindered performance in children with DS, who retained less when tested after a nap, but were more accurate after a wake interval. These effects of napping persisted 24 h later in both groups, even after an intervening overnight period of sleep. During naps in typical children, memory retention for object-label associations correlated positively with percent of time in rapid eye movement (REM) sleep. However, in children with DS, a population with reduced REM, learning was impaired, but only after the nap. This finding shows that a nap can increase memory loss in a subpopulation, highlighting that naps are not universally beneficial. Further, in healthy preschooler's naps, processes in REM sleep may benefit learning.

Curiosity-driven memory enhancement persists over time but does not benefit from post-learning sleep.

Sleep-dependent memory processing is dependent on several factors at learning, including emotion, encoding strength, and knowledge of future relevance. Recent work documents the role of curiosity on learning, showing that memory associated with high-curiosity encoding states is retained better and that this effect may be driven by activity within the dopaminergic circuit. Here, we examined whether this curiosity effect was enhanced by or dependent on sleep-related consolidation. Participants learned the answers to trivia questions that they had previously rated on a curiosity scale, and they were shown faces between each question and answer presentation. Memory for these answers and faces was tested either immediately or after a 12-hour delay containing sleep or wakefulness, and polysomnography data was collected for a subset of the sleep participants. Although the curiosity effect for both the answers and incidentally-learned faces was replicated in immediate tests and after the 12-hour delay, the effect was not impacted by the presence of sleep in either case, nor did the effect show a relationship with total sleep time or time in slow-wave sleep. This study suggests that curiosity may be a learning factor that is not subsequently affected by sleep-dependent memory consolidation, but more work ought to examine the role of sleep on curiosity-driven memory in other contexts.

Learning Without Trying: The Clinical Relevance of Statistical Learning.

Purpose: Statistical learning research seeks to identify the means by which learners, with little perceived effort, acquire the complexities of language. In the past 50 years, numerous studies have uncovered powerful learning mechanisms that allow for learning within minutes of exposure to novel language input. Method: We consider the value of information from statistical learning studies that show potential for making treatment of language disorders faster and more effective. Results: Available studies include experimental research that demonstrates the conditions under which rapid learning is possible, research showing that these findings apply to individuals with disorders, and translational work that has applied learning principles in treatment and educational contexts. In addition, recent research on memory formation has implications for treatment of language deficits. Conclusion: The statistical learning literature offers principles for learning that can improve clinical outcomes for children with language impairment. There is potential for further applications of this basic research that is yet unexplored.

How who is talking matters as much as what they say to infant language learners.

Human vocalizations contain both voice characteristics that convey who is talking and sophisticated linguistic structure. Inter-talker variation in voice characteristics is traditionally seen as posing a challenge for infant language learners, who must disregard this variation when the task is to detect talkers' shared linguistic conventions. However, talkers often differ markedly in their pronunciation, vocabulary, and grammar. This is true even in monolingual environments, given factors like gender, dialect, and proficiency. We therefore asked whether infants treat the voice characteristics distinguishing talkers as a cue for learning linguistic conventions that one talker may follow more closely than another. Supporting this previously untested hypothesis, 12-month-olds did not freely combine two talkers' sentences distinguished by voice to more robustly learn the talkers' shared grammar rules. Rather, they used this voice information to learn rules to which only one talker adhered, a finding replicated in same-aged infants with greater second language exposure. Both language groups generalized the rules to novel sentences produced by a novel talker. Voice characteristics can thus help infants learn and generalize talker-dependent linguistic structure, which pervades natural language. Results are interpreted in light of theories linking language learning with voice perception.

Evaluation of the Effectiveness and Safety of Olanzapine as an Adjunctive Treatment for Anorexia Nervosa in Adolescents: An Open-Label Trial.

OBJECTIVES: To evaluate the effectiveness and safety of adjunctive olanzapine treatment for low weight adolescents with anorexia nervosa (AN). METHODS: A non-randomized open-label trial was conducted between 2010 and 2014. Participants received standard treatment and were invited to take olanzapine at study enrollment. Participants could accept, continue, or discontinue olanzapine as treatment progressed. Weight and psychological outcomes were monitored. RESULTS: Of 239 adolescents assessed, 65 met inclusion criteria, 38 enrolled in the study, and 32 were retained for analysis. Twenty-two participants took olanzapine (medication group) and ten participants did not (comparison group). Participants in the medication group demonstrated a higher rate of weight gain compared to those who did not receive olanzapine (p = .012). No serious adverse events were noted, although seven participants (31.8%) discontinued olanzapine due to a side effect. CONCLUSION: Preliminary results suggest that olanzapine may help facilitate weight gain in adolescents with AN. The importance of medical monitoring over the course of treatment is discussed. Evaluation of the Efficacy and Safety of Olanzapine for Anorexia Nervosa in Children and Adolescents; http://clinicaltrials.gov; NCT01184443.

OBJECTIFS: Évaluer l'efficacité et l'innocuité d'un traitement d'appoint par olanzapine pour les adolescents de faible poids souffrant d'anorexie mentale (AM). MÉTHODES: Un essai ouvert non randomisé a été mené entre 2010 et 2014. Les participants ont reçu un traitement standard et ont été invités à prendre de l'olanzapine lors de l'inscription à l'étude. Les participants pouvaient accepter, continuer ou cesser l'olanzapine à mesure que le traitement progressait. Le poids et les résultats psychologiques ont été surveillés. RÉSULTATS: Sur les 239 adolescents évalués, 65 satisfaisaient aux critères d'inclusion, 38 se sont inscrits à l'étude, et 32 ont été retenus pour analyse. Vingt-deux participants ont pris de l'olanzapine (groupe du médicament) et 10 participants n'en ont pas pris (groupe de comparaison). Les participants du groupe du médicament ont démontré un taux plus élevé de prise de poids comparativement à ceux qui n'ont pas reçu d'olanzapine (p = 0,012). Aucun effet indésirable sérieux n'a été noté, bien que 7 participants (31,8 %) aient cessé l'olanzapine en raison d'un effet secondaire. CONCLUSION: Les résultats préliminaires suggèrent que l'olanzapine peut aider à faciliter la prise de poids chez les adolescents souffrant d'AM. L'importance de la surveillance médicale en cours de traitement est discutée. Evaluation of the Efficacy and Safety of Olanzapine for Anorexia Nervosa in Children and Adolescents; http://clinicaltrials.gov; NCT01184443.

Losing memories during sleep after targeted memory reactivation.

Targeting memories during sleep opens powerful and innovative ways to influence the mind. We used targeted memory reactivation (TMR), which to date has been shown to strengthen learned episodes, to instead induce forgetting (TMR-Forget). Participants were first trained to associate the act of forgetting with an auditory forget tone. In a second, separate, task they learned object-sound-location pairings. Shortly thereafter, some of the object sounds were played during slow wave sleep, paired with the forget tone to induce forgetting. One week later, participants demonstrated lower recall of reactivated versus non-reactivated objects and impaired recognition memory and lowered confidence for the spatial location of the reactivated objects they failed to spontaneously recall. The ability to target specific episodic memories for forgetting during sleep has implications for developing novel therapeutic techniques for psychological disorders such as PTSD and phobias.

Brain correlates of memory reconsolidation: A role for the TPJ.

In this paper, we investigate the process by which new experiences reactivate and potentially update old memories. Such memory reconsolidation appears dependent on the extent to which current experience deviates from what is predicted by the reactivated memory (i.e. prediction error). If prediction error is low, the reactivated memory is likely to be updated with new information. If it is high, however, a new, separate, memory is more likely to be formed. The temporal parietal junction TPJ has been shown across a broad range of content areas (attention, social cognition, decision making and episodic memory) to be sensitive to the degree to which current information violates the observer's expectations - in other words, prediction error. In the current paper, we investigate whether the level of TPJ activation during encoding predicts if the encoded information will be used to form a new memory or update a previous memory. We find that high TPJ activation predicts new memory formation. In a secondary analysis, we examine whether reactivation strength - which we assume leads to a strong memory-based prediction - mediates the likelihood that a given individual will use new information to form a new memory rather than update a previous memory. Individuals who strongly reactivate previous memories are less likely to update them than individuals who weakly reactivate them. We interpret this outcome as indicating that strong predictions lead to high prediction error, which favors new memory formation rather than updating of a previous memory.