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Sleep quality is increasingly recognized as a potential factor influencing healthy cognitive and neural development across the lifespan. It is becoming more recognized as an important factor for persons with Down syndrome, and this chapter describes the most recent literature regarding sleep disturbance, its correlates, and findings from animal models in this population. The authors discuss the relation of poor sleep to behavioral, brain, and cognitive dysfunction and highlight the family consequences for altered sleep in children with Down syndrome. These pervasive sleep deficits have the potential to derail cognitive development during critical periods for language learning and could also exacerbate age-related cognitive decline. The authors hope that this compilation of evidence regarding sleep deficits in persons with Down syndrome will help facilitate more treatment studies for sleep disorders in this population, including treatments aimed at poor sleep in infants, as well as mid-adulthood, which may lessen or delay the impact of the pathological progression of Alzheimer’s disease. Methodological challenges to sleep research are discussed, and future directions for this field are highlighted.

The hippocampus is linked with both sleep and memory, but there is debate about whether a salient aspect of sleep – dreaming – requires its input. To address this question, we investigated if human patients with focal bilateral hippocampal damage and amnesia engaged in dreaming. We employed a provoked awakening protocol where participants were woken up at various points throughout the night, including during non-rapid eye movement and rapid eye movement sleep, to report their thoughts in that moment. Despite being roused a similar number of times, dream frequency was reduced in the patients compared to control participants, and the few dreams they reported were less episodic-like in nature and lacked content. These results suggest that hippocampal integrity may be necessary for typical dreaming to occur, and aligns dreaming with other hippocampal-dependent processes such as episodic memory that are central to supporting our mental life., eLife digest Dreaming has intrigued humans for thousands of years, but why we dream still remains somewhat of a mystery. Although dreams are not a precise replay of our memories, one idea is that dreaming helps people process past experiences as they sleep. If this is true, then part of the brain called the hippocampus that is important for memory should also be necessary for dreaming. Damage to the hippocampus can cause a condition called amnesia that prevents people from forming new memories and remembering past experiences. However, studies examining dreaming in people with amnesia have produced mixed results: some found that damage to the hippocampus had no effect on dreams, while others found it caused people to have repetitive dreams that lacked detail. One reason for these inconsistencies is that some studies asked participants about their dreams the next morning by which time most people, particularly those with amnesia, have forgotten if they dreamed. To overcome this limitation, Spanò et al. asked participants about their dreams immediately after being woken up at various points during the night. The experiment was carried out with four people who had damage to both the left and right hippocampus and ten healthy volunteers. Spanò et al. found that the people with hippocampal damage reported fewer dreams and the dreams they had were much less detailed. These findings suggest that a healthy hippocampus is necessary for both memory and dreaming, reinforcing the link between the two. Hippocampal damage is associated with a number of diseases, including dementia. If these diseases cause patients to dream less, this may worsen the memory difficulties associated with these conditions.

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.

A multisite study investigated the test-retest reliability and practice effects of a battery of assessments to measure neurocognitive function in individuals with Down syndrome (DS). The study aimed to establish the appropriateness of these measures as potential endpoints for clinical trials. Neurocognitive tasks and parent report measures comprising the Arizona Cognitive Test Battery (ACTB) were administered to 54 young participants with DS (7–20 years of age) with mild to moderate levels of intellectual disability in an initial baseline evaluation and a follow-up assessment 3 months later. Although revisions to ACTB measures are indicated, results demonstrate adequate levels of reliability and resistance to practice effects for some measures. The ACTB offers viable options for repeated testing of memory, motor planning, behavioral regulation, and attention. Alternative measures of executive functioning are required.

Recent studies have highlighted the dentate gyrus as a region of increased vulnerability in mouse models of Down syndrome (DS). It is unclear to what extent these findings are reflected in the memory profile of people with the condition. We developed a series of novel tasks to probe distinct medial temporal functions in children and young adults with DS, including object, spatial, and temporal order memory. Relative to mental age-matched controls (n = 45), individuals with DS (n = 28) were unimpaired on subtests involving short-term object or configural recall that was divorced from spatial or temporal contexts. By contrast, the DS group had difficulty recalling spatial locations when contextual information was salient and recalling the order in which objects were serially presented. Results are consistent with dysfunction of spatial and temporal contextual pattern separation abilities in individuals with DS, mediated by the hippocampus, including the dentate gyrus. Amidst increasing calls to bridge human and animal work, the memory profile demonstrated here in humans with DS is strikingly similar to that of the Ts65Dn mouse model of DS. The study highlights the trisynaptic circuit as a potentially fruitful intervention target to mitigate cognitive impairments associated with DS.

Lynn Nadel has been a trailblazer in memory research for decades. In just one example, Nadel and Zola-Morgan [Infantile amnesia, In Infant memory, Springer, Boston, MA, 1984, pp. 145-172] were the first to present the provocative notion that the extended development of the hippocampus may underlie the period of infantile amnesia. In this special issue of Hippocampus to honor Lynn Nadel, we review some of his major contributions to the field of memory development, with an emphasis on his observations that behavioral memory assessments follow an uneven, yet protracted developmental course. We present data emphasizing this point from memory-related eye movements [Hannula & Ranganath, Neuron, 2009, 63(5), 592-599]. Eye tracking is a sensitive behavioral measure, allowing for an indication of memory function even without overt responses, which is seemingly ideal for the investigation of memory in early childhood or in other nonverbal populations. However, the behavioral manifestation of these eye movements follows a U-shaped trajectory-and one that must be understood before these indictors could be broadly used as a marker of memory. We examine the change in preferential looking time to target stimuli in school-aged children and adults, and compare these eye movement responses to explicit recall measures. Our findings indicate change in the nature and timing of these eye movements in older children, causing us to question how 6-month-old infants may produce eye movements that initially appear to have the same properties as those measured in adulthood. We discuss these findings in the context of our current understanding of memory development, particularly the period of infantile amnesia.

Event related potentials (ERPs) can help to determine the cognitive and neural processes underlying memory functions and are often used to study populations with severe memory impairment. In healthy adults, memory is typically assessed with active tasks, while in patient studies passive memory paradigms are generally used. In this study we examined whether active and passive continuous object recognition tasks measure the same underlying memory process in typically developing (TD) adults and in individuals with Down syndrome (DS), a population with known hippocampal impairment. We further explored how ERPs in these tasks relate to behavioral measures of memory. Data-driven analysis techniques revealed large differences in old-new effects in the active versus passive task in TD adults, but no difference between these tasks in DS. The group with DS required additional processing in the active task in comparison to the TD group in two ways. First, the old-new effect started 150 ms later. Second, more repetitions were required to show the old-new effect. In the group with DS, performance on a behavioral measure of object-location memory was related to ERP measures across both tasks. In total, our results suggest that active and passive ERP memory measures do not differ in DS and likely reflect the use of implicit memory, but not explicit processing, on both tasks. Our findings highlight the need for a greater understanding of the comparison between active and passive ERP paradigms before they are inferred to measure similar functions across populations (e.g., infants or intellectual disability).

Adults with Down syndrome (DS) are predisposed to obstructive sleep apnoea (OSA), but the effectiveness and acceptability of continuous positive airway pressure treatment (CPAP) in this group has rarely been formally assessed. This study was designed as a pilot randomised, parallel controlled trial for one month, continuing as an uncontrolled cohort study whereby the control group also received the intervention. Symptomatic, community-dwelling DS individuals exhibiting ≥10 apnoeas/hypopneas per hour in bed on a Type 3 home sleep study were invited to participate in this study, with follow-up at 1, 3, 6, and 12 months from baseline. Measurements of sleepiness, behaviour, cognitive function and general health were undertaken; the primary outcome was a change in the pictorial Epworth Sleepiness Scale (pESS) score. Twenty-eight participants (19 male) were enrolled: age 28 ± 9 year; body mass index 31.5 ± 7.9 kg/m2; 39.6 ± 32.2 apnoeas/hypopneas per hour in bed; pESS 11 ± 6/24. The pilot randomised controlled trial at one month demonstrated no change between the groups. At 12 months, participant (p = 0.001) pESS and Disruptive (p < 0.0001), Anxiety/Antisocial (p = 0.024), and Depressive (p = 0.008) behaviour scores were reduced compared to baseline. Improvement was noted in verbal (p = 0.001) and nonverbal intelligence scores (p = 0.011). General health scores also improved (p = 0.02). At the end of the trial, 19 participants continued on treatment. Use of CPAP in adults with DS and OSA led to a number of significant, sustained improvements in sleepiness and behavioural/emotional outcomes at 12 months.

The hippocampus plays a critical role in sleep-related memory processes [1, 2, 3], but it is unclear which specific sleep features are dependent upon this brain structure. The examination of sleep physiology in patients with focal bilateral hippocampal damage and amnesia could supply important evidence regarding these links. However, there is a dearth of such studies, despite these patients providing compelling insights into awake cognition [4, 5]. Here, we sought to identify the contribution of the hippocampus to the sleep phenotype by characterizing sleep via comprehensive qualitative and quantitative analyses in memory-impaired patients with selective bilateral hippocampal damage and matched control participants using in-home polysomnography on 4 nights. We found that, compared to control participants, patients had significantly reduced slow-wave sleep—likely due to decreased density of slow waves—as well as slow-wave activity. In contrast, slow and fast spindles were indistinguishable from those of control participants. Moreover, patients expressed slow oscillations (SOs), and SO-fast spindle coupling was observed. However, on closer scrutiny, we noted that the timing of spindles within the SO cycle was delayed in the patients. The shift of patients’ spindles into the later phase of the up-state within the SO cycle may indicate a mismatch in timing across the SO-spindle-ripple events that are associated with memory consolidation [6, 7]. The substantial effect of selective bilateral hippocampal damage on large-scale oscillatory activity in the cortex suggests that, as with awake cognition, the hippocampus plays a significant role in sleep physiology, which may, in turn, be necessary for efficacious episodic memory.

Recent work suggests that memory representations may guide basic perceptual functions, such as figure-ground perception. In three studies we assessed top-down contributions to figure-ground perception in typical development and in two developmental disorders: Down syndrome (DS) and autism (ASD). We investigated how figure-ground segregation is modulated by high-level cues (i.e., memory representations) and low-level cues (i.e., convexity and surface integration). Study 1 results showed that both high-level and low-level contributions to figure-ground perception are functional by the age of 4 years. In Study 2, individuals with DS exhibited intact figure-ground segregation based on low level cues when compared with mental age–matched participants, but they showed attenuated effects of high-level memory cues on figure-ground assignment. In Study 3, individuals with ASD showed intact effects of both high-level and low-level cues on figure-ground perception, counter to previous suggestions that high-level influences on perception are usually impaired in ASD.

This study examined individual differences in ADHD symptoms and executive function (EF) in children with Down syndrome (DS) in relation to the dopamine receptor D4 (DRD4) gene, a gene often linked to ADHD in people without DS. Participants included 68 individuals with DS (7-21 years), assessed through laboratory tasks, caregiver reports, and experimenter ratings. Saliva samples were collected from the DS group and 66 children without DS to compare DRD4 allele distribution, showing no difference between the groups. When the sample with DS was stratified for ethnicity (n = 32), the DRD4 7-repeat allele significantly related to parent and experimenter ratings, but not to laboratory assessments. These results suggest that nontrisomy genetic factors may contribute to individual differences in ADHD symptoms in persons with DS.

Spatial context supports memory retrieval in adults. To understand the development of these effects, context effects on object recognition were tested in neurotypical children ages 3 years to adulthood (n 3–6 years = 34, n 10–16 years = 32, n college age = 22) and individuals with Down syndrome (DS) ages 10–29 years (n = 21). Participants engaged in an object recognition task; objects were presented in scenes and either remained in that same scene or were removed at test. In some groups (

Objectives To evaluate sleep consolidation and circadian activity rhythms in infants and toddlers with Down syndrome (DS) under light and socially entrained conditions within a familiar setting. Given previous human and animal data suggesting intact circadian regulation of melatonin across the day and night, it was hypothesized that behavioral indices of circadian rhythmicity would likewise be intact in the sample with DS. Methods A cross-sectional study of 66 infants and young children with DS, aged 5–67 months, and 43 typically developing age-matched controls. Sleep and measures of circadian robustness or timing were quantified using continuous in-home actigraphy recordings performed over seven days. Circadian robustness was quantified via time series analysis of rest-activity patterns. Phase markers of circadian timing were calculated alongside these values. Sleep efficiency was also estimated based on the actigraphy recordings. Results This study provided further evidence that general sleep quality is poor in infants and toddlers with DS, a population that has sleep apnea prevalence as high as 50% during the preschool years. Despite poor sleep quality, circadian rhythm and phase were preserved in children with DS and displayed similar developmental trajectories in cross-sectional comparisons with a typically developing (TD) cohort. In line with past work, lower sleep efficiency scores were quantified in the group with DS relative to TD children. Infants born with DS exhibited the worst sleep fragmentation; however, in both groups, sleep efficiency and consolidation increased across age. Three circadian phase markers showed that 35% of the recruitment sample with DS was phase-advanced to an earlier morning schedule, suggesting significant within-group variability in the timing of their daily activity rhythms. Conclusions Circadian rhythms of wake and sleep are robust in children born with DS. The present results suggest that sleep fragmentation and any resultant cognitive deficits are likely not confounded by corresponding deficits in circadian rhythms., Highlights • Circadian activity rhythms are robust in young children with Down syndrome. • Early morning activity is phase-advanced in a subgroup. • Infants with Down syndrome show significant sleep fragmentation. • Sleep efficiency improves with age in children with Down syndrome, but still lags the trajectory seen in typical development.

Recent studies have suggested that Boundary Extension (BE), a scene construction error, may be linked to the function of the hippocampus. In this study, we tested BE in two groups with variations in hippocampal development and disorder: a typically developing sample ranging from preschool to adolescence and individuals with Down syndrome. We assessed BE across three different test modalities: drawing, visual recognition, and a 3D scene boundary reconstruction task. Despite confirmed fluctuations in memory function measured through a neuropsychological assessment, the results showed consistent BE in all groups across test modalities, confirming the near universal nature of BE. These results indicate that BE is an essential function driven by a complex set of processes, that occur even in the face of delayed memory development and hippocampal dysfunction in special populations.

The memory profile of individuals with Down syndrome (DS) has mainly been examined through traditional laboratory tasks, often revealing substantial deficits in episodic and declarative memory. Little is known about the relation between memory abilities as measured in the laboratory versus naturalistic settings in this population, and no questionnaire assessments of everyday memory have been formally validated for this group. The current study's aims were twofold: 1) to describe the psychometric characteristics of a parent-reported everyday memory measure (the Observer Memory Questionnaire - Parent Form, OMQ-PF) in this population with known hippocampal and memory impairment (i.e., DS, ages 7-35 years), and 2) to determine if the measure has the sensitivity to detect impairments, thus providing some of the first data to document parent reports of everyday memory in individuals with DS. The results indicate that this scale is a reliable instrument for detecting and tracking memory deficits over time in this population. We found a correlation between parent reports of everyday memory difficulties and well-replicated deficits in a laboratory-based memory task (i.e., place-object paired associates learning). Our results suggest that the OMQ-PF has the potential to be used as a tool to help to track the status of memory function in this group both for use in descriptive studies and in studies of behavior and pharmacological intervention.

Background While it has been common practice to discourage second language learning in neurodevelopmental disorders involving language impairment, little is known about the effects of second language exposure (SLE) on broader cognitive function in these children. Past studies have not found differences on language tasks in children with Down syndrome (DS) and SLE. We expand on this work to determine the effects on the broader cognitive profile, including tests tapping deficits on neuropsychological measures of prefrontal and hippocampal function. Method This study examined the specific cognitive effects of SLE in children with DS (aged 7–18 years). Children with SLE (n = 13: SLE predominantly Spanish) and children from monolingual homes (n = 28) were assessed on a standardised battery of neuropsychological tests developed for DS, the Arizona Cognitive Test Battery. The current exposure level to a language other than English in the SLE group was greater than 4 h per day on average. Results No group differences were observed for any outcome, and level of exposure was also not linearly related to neuropsychological outcomes, several of which have been shown to be impaired in past work. Conclusion There were no measurable effects of SLE on neuropsychological function in this sample of children with DS. Potential clinical implications of these findings are discussed.

Background Recent studies have demonstrated that individuals with Down syndrome (DS) present both central and verbal working memory deficits compared with controls matched for mental age, whereas evidence on visuospatial working memory (VSWM) has remained ambiguous.The present paper uses a battery of VSWM tasks to test the hypothesis that individuals with DS can also encounter specific difficulties in VSWM. Method Four tasks were administered to 34 children and adolescents with DS and 34 controls matched for verbal mental age. In two of these tasks, participants had to remember a series of locations sequentially presented on a matrix (spatialsequential WM); in another two, they had to remember locations simultaneously presented (spatial-simultaneous WM). Results and Conclusions Results showed that individuals with DS are poorer than controls in the spatial-simultaneous tasks, but not in the spatialsequential tasks.These findings were not due to a difference in speed of visuospatial processing. In fact, when performances of the two groups in VSWM were compared using speed measures as covariates, differences between groups remained. It is suggested that the simultaneous VSWM deficit of individuals with DS could be due to the request for processing more than one item at a time.

Recent evidence has suggested that sleep may facilitate language learning. The current study examined variation in language ability in 29 toddlers with Down syndrome (DS) in relation to levels of sleep disruption. Toddlers with DS and poor sleep (66%, n = 19) showed greater deficits on parent-reported and objective measures of language, including vocabulary and syntax. Correlations between sleep and language were found in groups with equivalent medical and social backgrounds and after control for relevant behavioral co-morbidities, including autism symptoms. These results emphasize the important role of quality sleep in all children’s expressive language development, and may help increase our understanding of the etiology of language deficits in developmental disorders, potentially leading to new treatment approaches.

Aim Good-quality sleep is essential for normal learning and memory. Sleep fragmentation and disrupted sleep architecture are commonly observed throughout the lifespan of individuals with Down syndrome, a condition marked by cognitive deficits emerging within the first few months of life. While obstructive sleep apnea syndrome (OSAS) is known to contribute to the loss of sleep quality in Down syndrome, its relation to cognitive and behavioral impairment remains poorly understood. Method Using ambulatory polysomnography, we measured sleep in an unreferred community-based sample of 38 individuals with Down syndrome (15 males, 23 females; mean age 9y 7mo (SD 1y 9mo), range 7–12y). Cognitive outcomes were assessed with the Arizona Cognitive Test Battery, a set of psychometric measures designed and validated for this population. Results Among children with Down syndrome, mean Verbal IQ score (p=0.006) was 9 points lower in those with comorbid OSAS (apnea–hypopnea index >1.5) than in those without OSAS, and performance on measures of cognitive flexibility was poorer (p=0.03). In addition, those with OSAS showed increased light-stage sleep (p=0.009) at the expense of slow-wave sleep (p=0.04). Interpretation These findings demonstrate a relation between OSAS and cognitive outcomes in Down syndrome. More work is required to fully understand the mechanisms underlying the links between poor sleep and impaired cognitive function. Overall, these findings highlight the importance of adequate sleep in typically and atypically developing populations.

The high prevalence of sleep disorders, particularly obstructive sleep apnea, is well established in children with Down syndrome. However, only a few studies have focused on older children and young adults in this population. Given the presence of sleep disorders and the early emergence of Alzheimer's disease, more work is needed to examine the relationship between sleep and cognition in Down syndrome. Twenty-nine adolescents and young adults with Down syndrome participated in the present study. Parents reported on their sleep difficulties using a well-validated measure of sleep problems in intellectual disabilities. Based on theoretical models linking obstructive sleep apnea to prefrontal cortex dysfunction, we tested components of executive functions that have been shown to be impaired in previous studies of Down syndrome. First, results indicate that participants with Down syndrome with higher body mass index also had increased caregiver reports of sleep apnea symptoms. Individuals with high ratings of sleep disruption also showed greater difficulties with executive function. These results suggest that sleep disruption may place this set of functions at risk in young adults. Future work should examine if this risk may result in earlier onset of dementia or steeper decline with Alzheimer's disease. Further, additional studies are needed to investigate the effect of exercise interventions and weight reduction on sleep disorders in this population.

The study of cognitive function in Down syndrome (DS) has advanced rapidly in the past decade. Mouse models have generated data regarding the neurological basis for the specific cognitive profile of DS (i.e., deficits in aspects of hippocampal, prefrontal, and cerebellar function) and have uncovered pharmacological treatments with the potential to affect this phenotype. Given this progress, the field is at a juncture in which we require assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this chapter, we describe the cognitive profile of humans with DS and associated mouse models, discussing the ways in which we may merge these findings so as to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed.