Approximate additions and working memory in individuals with Down syndrome

There is some evidence that individuals with Down syndrome (DS) may have a poorer mathematical performance and a poorer working memory (WM) than typically developing (TD) children of the same mental age. In both typical and atypical individuals, different aspects of arithmetic and their relationships with WM have been largely studied, but the specific contribution of WM to the representation and elaboration of non-symbolic quantities has received little attention. The present study examined whether individuals with DS are as capable as TD children matched for fluid intelligence of estimating numerosity both of single sets and of added sets resulting when two sequentially presented sets are added together, also considering how these tasks related to verbal and visuospatial WM. Results showed that the DS group's performance was significantly worse than the TD group's in numerosity estimation involving one set, but not when estimating the numerosity resulting from the addition. Success in the addition task was related to success in the working memory tasks, but only for the group with DS; this applied especially to the visuospatial component, which (unlike the verbal component) was not impaired in the group with DS. It is concluded that the two numerosity tasks involve different processes. It is concluded that the arithmetical and working memory difficulties of individuals with DS are not general, and they can draw on their WM resources when estimating the numerosity of additions.     

Verbal and visuospatial working memory deficits in children with Down syndrome

The hypothesis that deficits of children with Down syndrome on working memory tasks are more evident the higher the control required and for verbal than visuospatial tasks was tested. Two groups of children, one with Down syndrome, who ranged in age from 7 to 18, and a control group were assessed with batteries of verbal and visuospatial working memory tests requiring different levels of control. On tasks requiring low control, children with Down syndrome showed impairment of verbal but not visuospatial working memory tasks. As the requirement for control increased, they showed greater impairment on both tasks. Children with Down syndrome were comparatively better in visuospatial than verbal tasks. Implications of these results for working memory models and the role of working memory in intelligence were discussed.     

A specific deficit in visuospatial simultaneous working memory in Down syndrome

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 (spatial-sequential 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 spatial-sequential 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.     

Spatial-simultaneous and spatial-sequential working memory in individuals with Down syndrome: The effect of configuration

Earlier research showed that visuospatial working memory (VSWM) is better preserved in Down syndrome (DS) than verbal WM. Some differences emerged, however, when VSWM performance was broken down into its various components, and more recent studies revealed that the spatial-simultaneous component of VSWM is more impaired than the spatial-sequential one. The difficulty of managing more than one item at a time is also evident when the information to be recalled is structured. To further analyze this issue, we investigated the advantage of material being structured in spatial-simultaneous and spatial-sequential tasks by comparing the performance of a group of individuals with DS and a group of typically-developing children matched for mental age.Both groups were presented with VSWM tasks in which both the presentation format (simultaneous vs. sequential) and the type of configuration (pattern vs. random) were manipulated.Findings indicated that individuals with DS took less advantage of the pattern configuration in the spatial-simultaneous task than TD children; in contrast, the two groups’ performance did not differ in the pattern configuration of the spatial-sequential task.Taken together, these results confirmed difficulties relating to the spatial-simultaneous component of VSWM in individuals with DS, supporting the importance of distinguishing between different components within this system. The findings are discussed in terms of factors influencing this specific deficit.     

Frontal cortex as the central executive of working memory: time to revise our view

For historical reasons (Bianchi, 1895; Harlow, 1968; Luria, 1966; Shallice, 1982), a specific link between the central executive of working memory and the frontal cortex was originally suggested by Baddeley (1986). This review discusses the evidence against such a univocal link. Two executive processes investigated in neuropsychology are discussed: inhibition (WCST, Stroop, proactive interference, go-no go, Stop signal and the Hayling test) and dual-task management. The evidence reviewed demonstrates (i) that executive processes involve links between different brain areas, not exclusively with the frontal cortex, (ii) that patients with no evidence of frontal damage present with executive deficits, and (iii) that patients with frontal lesions do not always show executive deficits. In conclusion, this review suggests that it is time for a more dynamic and flexible view of the neural substrate of executive processes to be considered. It also confirms, as recently suggested by Baddeley (1996, 1998a, 1998b), that the study of frontal patients cannot be used as a primary source of evidence to understand CE functions.     

Frontal theta activity in humans increases with memory load in a working memory task

Recent theoretical work has suggested that brain oscillations in the theta band are involved in active maintenance and recall of working memory representations. To test this theoretical framework we recorded neuromagnetic responses from 10 subjects performing the Sternberg task. Subjects were required to retain a list of 1, 3, 5 or 7 visually presented digits during a 3-s retention period. During the retention period we observed ongoing frontal theta activity in the 7-8.5-Hz band recorded by sensors over frontal brain areas. The activity in the theta band increased parametrically with the number of items retained in working memory. A time-frequency analysis revealed that the task-dependent theta was present during the retention period and during memory scanning. Following the memory task the theta activity was reduced. These results suggest that theta oscillations generated in frontal brain regions play an active role in memory maintenance.     

Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease

Introduction - Inflammatory processes are suspected in the pathomechanism of Alzheimer's dementia (AD) but the serum and cerebrospinal fluid (CSF) levels of inflammatory cytokines are not yet determined in the different forms of the disorder. Subjects and methods - Interleukin-6 (IL-6) levels were examined in the sera and CSF of patients with mild-moderate and severe stage of late onset sporadic type of AD and in the sera of demented Down syndrome (DS) probands with similar stages of AD and compared with data of age-matched healthy controls. Results - Normal serum IL-6 levels were found in the mild-moderate stage, but significantly increased levels were found in the severe stage of both dementia groups. The CSF concentrations remained within the normal range in all groups. Positive correlations between the serum IL-6 levels and age and the severity of the disease were present. Conclusion - These findings suggest a disease stage dependent general activation of the immune system both in sporadic AD and in DS with AD.     

Syntactic comprehension and working memory in children with specific language impairment,autism or Down syndrome

This study examined syntactic assignment for predicates and reflexives as well as working memory effects in the sentence comprehension of children with Specific Language Impairment (SLI), Down syndrome (DS), high functioning Autism (HFA) and Typical Language Development (TLD). Fifty-seven children (35 boys and 22 girls) performed a computerised picture-selection sentence comprehension task. Predicate attachment and reflexive antecedent assignment (with working memory manipulations) were investigated. The results showed that SLI, HFA and DS children exhibited poorer overall performance than TLD children. Children with SLI exhibited similar performance to the DS and HFA children only when working memory demands were higher. We conclude that children with SLI, HFA and DS differ from children with TLD in their comprehension of predicate and reflexive structures where the knowledge of syntactic assignment is required. Working memory manipulation had different effects on syntactic comprehension depending on language disorder. Intelligence was not an explanatory factor for the differences observed in performance.     

Improving memory span in children with Down syndrome

Background Down syndrome (DS) is characterized by impaired memory span, particularly auditory verbal memory span. Memory span is linked developmentally to several language capabilities, and may be a basic capacity that enables language learning. If children with DS had better memory span, they might benefit more from language intervention. The present study evaluates a home‐based parent‐implemented intervention designed to improve auditory memory span in children with DS. Method Sixteen children with DS, age 6–14, completed one or two 3‐month periods of memory training using overt cumulative rehearsal and auditory‐only procedures. Children were divided into two groups. Group 1 completed 3 months of memory training followed by 3 months of visual activities, followed by three more months of memory training. Group 2 had the opposite schedule. Before and after each 3‐month period, children came into the laboratory for memory assessment. Results Children improved in training sessions and a small amount on digit span, the primary proximal outcome assessment measure. Digit span improvement was linked to the memory training, as indicated by control comparisons and correlations. Improvement was correlated with language comprehension and verbal working memory, but not with non‐verbal ability, age or home/behavioural variables. No improvement was evident on distal outcome measures (sentence memory and verbal working memory); however, a phonological similarity effect emerged coincidence with memory training, suggesting increased use of phonological codes in memory. Conclusions Results suggest that some children with DS can improve their auditory verbal memory span with home‐based rehearsal training, at least in limited ways. Children with good language and verbal working memory skills may be the best candidates for this type of training, even though they may show only small improvements. Still, small improvements in a severely impaired function are noteworthy, and justify further investigation.     

The medial temporal memory system in Down syndrome: Translating animal models of hippocampal compromise

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.     

Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain

There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na⁺/K⁺ ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6 days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.     

The cerebral cortex in fetal Down syndrome

Brain histopathology of 32 fetuses with Down syndrome was compared to that of 25 age-matched normal controls and 9 brains of fetuses of HIV positive mothers. Four cases of Down syndrome and 1 HIV case showed microdysgenesia of the cerebral cortex. As the pathogenetic background of cortical irregularities is presently not known, we analyzed the neuronal expression of drebrin, an actin-binding protein of neuronal dendritic spines. This protein is thought to play a role in synaptic formation and was recently shown to be manifold reduced in brains of fetuses with Down syndrome. However, immunocytochemistry revealed no differences in drebrin expression pattern between Down patients and controls. We conclude that cerebral cortical microdysgenesia is an infrequent non-specific pathology in fetal Down syndrome.     

Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms

Levels of brain-derived neurotrophic factor (BDNF) are reduced in specific brain regions in Alzheimer's disease (AD) and BDNF gene polymorphisms have been suggested to influence AD risk, hippocampal function, and memory. We investigated whether the polymorphisms at the BDNF 196 and 270 loci were associated with AD in a clinical and neuropathological cohort of 116 AD cases and 77 control subjects. To determine how BDNF protein levels relate to BDNF polymorphisms and AD pathology, we also measured BDNF in temporal association cortex, frontal association cortex, and cerebellum in 57 of the AD and 21 control cases. BDNF protein levels in temporal neocortex of the AD brains were reduced by 33% compared to control brains, whereas levels were unchanged in frontal and cerebellar cortex. The BDNF genotypes were not significantly associated with a diagnosis of AD, although the BDNF 270 C allele was slightly overrepresented among carriers of the APOEepsilon4 allele. Moreover, BDNF protein levels did not differ between the various BDNF genotypes and alleles. Neuropathologically, the loss of BDNF in AD showed a weak correlation with accumulation of neuritic amyloid plaques and loss of the neuronal/synaptic marker synaptophysin. The results suggest that the investigated BDNF polymorphisms are neither robust genetic risk factors nor determinants of BDNF protein levels in AD.     

Episodic-like memory in Ts65Dn, a mouse model of Down syndrome

Ts65Dn mice, like individuals with Down syndrome (DS), demonstrate a functional dissociation between explicit and implicit forms of memory, showing selective impairment in explicit or declarative learning tasks. Here, we explored Ts65Dn explicit memory deficits further by evaluating the ability of these mice to assimilate the temporal and spatial contexts under which previously novel objects had been encountered. We found that Ts65Dn mice could in fact form contextual representations of objects over the course of a few hours, contrary to their inability to discriminate object novelty over a more prolonged period of 24h. These results suggest that Ts65Dn mice might have particular difficulties in declarative tasks requiring long-term memory, presenting an especially important putative therapeutic target for pre-clinical and clinical DS research.     

A large-scale neurocomputational model of task-oriented behavior selection and working memory in prefrontal cortex

The prefrontal cortex (PFC) is crucially involved in the executive component of working memory, representation of task state, and behavior selection. This article presents a large-scale computational model of the PFC and associated brain regions designed to investigate the mechanisms by which working memory and task state interact to select adaptive behaviors from a behavioral repertoire. The model consists of multiple brain regions containing neuronal populations with realistic physiological and anatomical properties, including extrastriate visual cortical regions, the inferotemporal cortex, the PFC, the striatum, and midbrain dopamine (DA) neurons. The onset of a delayed match-to-sample or delayed nonmatch-to-sample task triggers tonic DA release in the PFC causing a switch into a persistent, stimulus-insensitive dynamic state that promotes the maintenance of stimulus representations within prefrontal networks. Other modeled prefrontal and striatal units select cognitive acceptance or rejection behaviors according to which task is active and whether prefrontal working memory representations match the current stimulus. Working memory task performance and memory fields of prefrontal delay units are degraded by extreme elevation or depletion of tonic DA levels. Analyses of cellular and synaptic activity suggest that hyponormal DA levels result in increased prefrontal activation, whereas hypernormal DA levels lead to decreased activation. Our simulation results suggest a range of predictions for behavioral, single-cell, and neuroimaging response data under the proposed task set and under manipulations of DA concentration.     

The role of vocabulary, working memory and inference making ability in reading comprehension in Down syndrome

Thirteen children and young adults with Down syndrome (DS) completed tests of language and reading and their performance was compared to that of three control groups. Reading comprehension was confirmed to be a specific deficit in DS and found to be strongly correlated with underlying language skills. Although reading comprehension was more strongly related to language ability in the DS group, this was shown to be a function of more advanced word recognition rather than a characteristic of DS per se. Individuals with DS were found to have greater difficulty with inferential comprehension questions than expected given their overall comprehension ability and the reading profile associated with DS was found to be similar to that of children known as poor comprehenders. It is recommended that oral language training programs, similar to those that have been shown to improve reading comprehension in poor comprehenders, be trialed with children who have DS.     

Verbal intrusions precede memory decline in adults with Down syndrome

Background Verbal intrusion errors are irrelevant responses made in the course of verbal memory retrieval or language production that have been associated with disruption of executive functions and the prefrontal cortex. They have been observed to occur more frequently both with normal aging and with neurodegenerative diseases such as Alzheimer's disease (AD). The purpose of this study was to longitudinally examine the production of verbal intrusions among middle‐aged adults with Down syndrome (DS) and unspecified intellectual disability (ID) to determine whether producing verbal intrusions at one point in time was related to subsequent verbal memory performance. Because of the combination of a relative deficit in verbal working memory (WM), premature aging, and higher risk of AD among adults with DS, it was predicted that they would make more verbal intrusions than adults with unspecified ID. Methods Word List recall (WLR), the Selective Reminding Test (SRT), and the Cued Recall Test (CRT), were administered three times at 18‐month intervals during a 3‐year period. In Analysis 1, aetiology differences in making intrusion errors were examined. Twenty‐three adults with unspecified ID in the moderate to mild range [time 1(T1) mean age = 47.2 years] and 42 adults with DS (T1 mean age = 44.3) participated. WLR is a serial WM task beginning at two word sequences and progressively increasing by one word every three trials. WLR intrusions were analysed because they were least likely to include ‘educated guesses’ because this test is not based on semantic categories. In Analysis 2, we only examined participants with DS. They were divided into two groups, 16 individuals who made at least one intrusion error at T1 (T1 mean age = 45.8) and 26 who did not (T1 mean age = 43.3). Longitudinal performance for these groups was analysed to determine whether the group that intruded at T1 did more poorly on subsequent memory tests. Results A higher proportion of responses comprised intrusions for the group with DS and a higher percentage of the participants with DS made at least one intrusion error when compared with participants with unspecified ID (74% and 44% respectively). Those participants with DS who made at least one intrusion error at T1 showed a subsequent decline in performance on both WLR and the SRT. Conclusions The production of intrusion errors during a verbal WM task is a characteristic of middle‐aged adults with DS. This suggests compromised executive function and control of inhibition within the verbal modality for this group. Further, verbal intrusions are a qualitative aspect of verbal processing that merit attention in considering the issue of deficiencies of language and verbal WM abilities among people with DS. Last, and perhaps most importantly, although not definitive diagnostically, an increase in verbal intrusions is a potentially noteworthy signal when evaluating the cognitive health of adults with DS.     

Increased serum neopterin levels in adults with Down syndrome

We quantitated serum neopterin levels in Down syndrome (DS), normal controls, Alzheimer's disease, multiple sclerosis and other neurological diseases. We then analyzed the relationships with age, sex, apolipoprotein E (Apo E) phenotype, and amyloid beta protein 1-40 (Abeta40) and 1-42 (Abeta42) levels. Neopterin levels were higher in DS than all other groups. Levels in young DS (< 40 years of age) and old DS (> 41 years) were similar. There was no significant correlation between neopterin levels and age, sex, Apo E phenotype, and Abeta40 or Abeta42 levels in DS. This lack of correlation between neopterin and Abeta levels suggests that the higher neopterin concentrations in DS group reflect inflammatory cell activation rather than AD neuropathology.