Verbal, visual, and spatio-sequential short-term memory: assessment of the storage capacities of children and teenagers with Down's syndrome

Background   It is recognized that individuals with Down's syndrome have a specific deficit in verbal short-term memory. On the other hand, non-verbal short-term memory seems to be preserved or even be a strong point for these persons. Nevertheless, the extent and specificity of the deficit must be determined. To do so, we carried out a research programme that allowed us to simultaneously assess various short-term memory systems in a developmental perspective, and to compare our participants' performance to that obtained by typically developing individuals of the same mental age.
Method   Three span tasks are used (auditory word span/visual patterns test/Corsi blocks task) with 54 children and teenagers with Down's syndrome and 54 typically developing children as control group. Participants were matched according to their cognitive level.
Results   For the auditory word span task, participants with Down's syndrome obtained performances significantly lower than those of the typically developing participants. On the other hand, compared with typically developing children, children and teenagers with Down's syndrome have a spatio-sequential span significantly higher for the lowest developmental ages. No significant differences were found for visual span.
Conclusions   Individuals with Down's syndrome exhibited a distinctive pattern of memory performance, in addition to their developmental specificities.     

Encoding and the frontal lobes: a dissociation between retrograde and anterograde memories

Recent functional neuroimaging studies have suggested that different neural substrates within the frontal lobes are associated with memory encoding, retrieval and monitoring. If this is the case, then it should be possible to find frontal patients with selective deficits to these processes. However, most laboratory based memory tests (e.g. Wechsler Memory Scale) require a combination of all these processes making it hard to find clear dissociations between patients. Using tests of everyday memory, this study documents a clear dissociation between a frontal patient's (JB) impaired ability to retrieve events from the anterograde period relative to spared ability to retrieve events from the retrograde period. This is consistent with specific disruption to frontal mechanisms associated with encoding which disrupts the formation of new episodic memories. The defective mechanism may be related to more general aspects of cognitive processing (e.g. selection demands), but it is unlikely to reflect damage to working memory (as assessed by the n-back task) as there is a clear dissociation between spared performance on this task and impaired performance on a comparable episodic recognition memory task.     

Disentangling working memory processes during spatial span assessment: A modeling analysis of preferred eye movement strategies

The neurocognitive processes involved during classic spatial working memory (SWM) assessment were investigated by examining naturally preferred eye movement strategies. Cognitively healthy adult volunteers were tested in a computerized version of the Corsi Block-Tapping Task—a spatial span task requiring the short term maintenance of a series of locations presented in a specific order—coupled with eye tracking. Modeling analysis was developed to characterize eye-tracking patterns across all task phases, including encoding, retention, and recall. Results revealed a natural preference for local gaze maintenance during both encoding and retention, with fewer than 40% fixated targets. These findings contrasted with the stimulus retracing pattern expected during recall as a result of task demands, with 80% fixated targets. Along with participants’ self-reported strategies of mentally “making shapes,” these results suggest the involvement of covert attention shifts and higher order cognitive Gestalt processes during spatial span tasks, challenging instrument validity as a single measure of SWM storage capacity.     

Dynamic working memory performance in individuals with single-domain amnestic mild cognitive impairment

Previous studies have observed poorer working memory performance in individuals with amnestic mild cognitive impairment than in healthy older adults. It is unclear, however, whether these difficulties are true only of the multiple-domain clinical subtype in whom poorer executive functioning is common. The current study examined working memory, as measured by the self-ordered pointing task (SOPT) and an n-back task, in healthy older adults and adults with single-domain amnestic mild cognitive impairment (aMCI). Individuals with single-domain aMCI committed more errors and required longer to develop an organizational strategy on the SOPT. The single-domain aMCI group did not differ from healthy older adults on the 1-back or 2-back, but had poorer discrimination on the 3-back task. This is, to our knowledge, the first characterization of dynamic working memory performance in a single-domain aMCI group. These results lend support for the idea that clinical amnestic MCI subtypes may reflect different stages on a continuum of progression to dementia and question whether standardized measures of working memory (span tasks) are sensitive enough to capture subtle changes in performance.     

Sustained and transient neural modulations in prefrontal cortex related to declarative long-term memory, working memory, and attention

Common activations in prefrontal cortex (PFC) during episodic and semantic long-term memory (LTM) tasks have been hypothesized to reflect functional overlap in terms of working memory (WM) and cognitive control. To evaluate a WM account of LTM-general activations, the present study took into consideration that cognitive task performance depends on the dynamic operation of multiple component processes, some of which are stimulus-synchronous and transient in nature; and some that are engaged throughout a task in a sustained fashion. PFC and WM may be implicated in both of these temporally independent components. To elucidate these possibilities we employed mixed blocked/event-related functional magnetic resonance imaging (fMRI) procedures to assess the extent to which sustained or transient activation patterns overlapped across tasks indexing episodic and semantic LTM, attention (ATT), and WM. Within PFC, ventrolateral and medial areas exhibited sustained activity across all tasks, whereas more anterior regions including right frontopolar cortex were commonly engaged in sustained processing during the three memory tasks. These findings do not support a WM account of sustained frontal responses during LTM tasks, but instead suggest that the pattern that was common to all tasks reflects general attentional set/vigilance, and that the shared WM-LTM pattern mediates control processes related to upholding task set. Transient responses during the three memory tasks were assessed relative to ATT to isolate item-specific mnemonic processes and were found to be largely distinct from sustained effects. Task-specific effects were observed for each memory task. In addition, a common item response for all memory tasks involved left dorsolateral PFC (DLPFC). The latter response might be seen as reflecting WM processes during LTM retrieval. Thus, our findings suggest that a WM account of shared PFC recruitment in LTM tasks holds for common transient item-related responses rather than sustained state-related responses that are better seen as reflecting more general attentional/control processes.     

Lipopolysaccharide-induced immune activation impairs attention but has little effect on short-term working memory

Cytokine-induced CNS inflammation has been theorized to contribute to cognitive dysfunction in sickness and neurodegenerative disease. We investigated the effects of systemic endotoxin-induced acute immune activation and inflammation on working memory and attention functions in pigeons assessed through two variations of an operant symbolic matching-to-sample (SMTS) task, employing doses of lipopolysaccharide (LPS) sufficient to induce fever. LPS produced moderate impairments in comparison to saline on the SMTS task designed to measure visual vigilance and attention, but the impairments were not as marked as those produced by chlordiazepoxide (CDP) which is known to disrupt attention. In contrast, LPS had no significant effect on short-term working memory performance compared to saline, while scopolamine, a cholinergic antagonist known to disrupt working memory, did impair performance. The results have implications for the cognitive impairments seen in illnesses characterized by chronic cytokine activation (e.g., Alzheimer's disease) as well as illnesses treated with cytokines (e.g., multiple sclerosis) suggesting that some cognitive failures attributed to working memory impairments per se may better be attributed to prior attention impairments.     

Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks

Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.     

Social working memory and its distinctive link to social cognitive ability: an fMRI study

Engaging social working memory (SWM) during effortful social cognition has been associated with neural activation in two neurocognitive systems: the medial frontoparietal system and the lateral frontoparietal system. However, the respective roles played by these systems in SWM remain unknown. Results from this study demonstrate that only the medial frontoparietal system supports the social cognitive demands managed in SWM. In contrast, the lateral frontoparietal system supports the non-social cognitive demands that are needed for task performance, but that are independent of the social cognitive computations. Moreover, parametric increases in the medial frontoparietal system, but not the lateral frontoparietal system, in response to SWM load predicted performance on a challenging measure of perspective-taking. Thus, the medial frontoparietal system may uniquely support social cognitive processes in working memory and the working memory demands afforded by effortful social cognition, such as the need to track another person’s perspective in mind.     

Event-based prospective memory failure in amnestic mild cognitive impairment

Prospective memory (PM) deficits have recently been documented in individuals with amnestic mild cognitive impairment (aMCI). In this paper, we investigated whether these deficits are due to the failure of retrospective memory processes. We also examined the role played by attentional/executive processes in PM functioning.We enrolled 24 individuals with aMCI and 24 healthy controls (NCs). In the PM procedure, we manipulated both the memory load of the retrospective component of the PM task and the complexity of the ongoing task in a 2 × 2 experimental design. Sequences of four words were presented. Participants had to repeat the sequence in the same order (low attentional demand condition) or in the reverse order (high attentional demand condition). When a target word appeared in the sequence, participants had to press a button on the keyboard (PM task). Target words could be one (low memory load condition) or four (high memory load condition) in different blocks.MCI participants obtained lower PM scores than NCs in all four experimental conditions. However, they recalled the target words less accurately than NCs only in one four-word condition. Finally, the executive demand of the ongoing task did not significantly affect the PM performance of aMCI individuals.Our findings confirm that PM is severely impaired in individuals with aMCI. Moreover, a failure of retrospective memory processes does not seem to fully account for the poor PM performance in aMCI individuals. Finally, the finding that in these individuals, a deficit in executive control cannot be claimed as the main responsible for the observed PM impairment could suggest the involvement of automatic-reflexive processes.     

Properties of delay-period neuronal activity in the primate prefrontal cortex during memory- and sensory-guided saccade tasks

The dorsolateral prefrontal cortex (DLPFC) is involved in visuospatial short-term (or working) memory. Its cellular basis has been widely examined using the delayed-response paradigm in nonhuman primates. Sustained delay-period activity in DLPFC neurons with directional difference (i.e. directional delay-period activity) has been thought to represent visuospatial short-term (or working) memory. However, little is known about the activity of these neurons during a delay period when the sensory input remains. To address this issue, we examined neuronal activity in the DLPFC while macaque monkeys performed a memory-guided saccade (MGS) task and a delayed visually guided saccade (VGS) task. The MGS task required a memory-guided saccade for a remembered target location. The VGS task had the same temporal sequence as the MGS task, but the sensory stimulus remained during the delay period. We found that most of the DLPFC neurons with directional delay-period activity showed sustained activation during the 'delay' period in the VGS task only ('V-neurons', 49%), or in both tasks ('MV-neurons', 46%). Neurons showing directional delay-period activity in the MGS task only ('M-neurons') were only 5% of the DLPFC neurons with directional delay-period activity. These findings indicate that most DLPFC neurons that are active during the delay period are also active when the sensory stimulus remains, suggesting that DLPFC neurons driven by mnemonic information are also driven by sensory input. Such sustained representation of information should have potential utility in flexible cognitive controls of behaviour.     

Delay-related cerebral activity and motor preparation

Flexible goal-oriented behavior requires the ability to carry information across temporal delays. This ability is associated with sustained neural firing. In cognitive terms, this ability has often been associated with the maintenance of sensory material online, as during short-term memory tasks, or with the retention of a motor code, as during movement preparation tasks. The general issue addressed in this paper is whether short-term storage of sensory information and preparation of motor responses rely on different anatomical substrates. We used functional magnetic resonance imaging (fMRI) to measure sustained and time-varying delay-related cerebral activity evoked during performance of a delay non-match to sample (DNMS) task, where task contingencies rather than explicit instructions ensured that either sensory or motor representations were used to cross the delay period on each trial. This approach allowed us to distinguish sensory from motor characteristics of delay-related activity evoked by task contingencies, rather than differences in the control of short-term storage driven by verbal instructions. Holding sensory material online evoked both sustained and time-varying delay-related activity in prefrontal regions, whereas movement preparation evoked delay-related responses in precentral areas. Intraparietal cortex was sensitive to the presence of memoranda, but indifferent to the type of information that was retained in memory. Our findings indicate that short-term storage of sensory information and preparation of motor responses rely on partially segregated cerebral circuits. In the frontal lobe, these circuits are organized along a rostro-caudal dimension, corresponding to the sensory or motor nature of the stored material.     

A stroke patient with impairment of auditory sensory (echoic) memory

A 42-year-old man suffered damage to the left supra-sylvian areas due to a stroke and presented with verbal short-term memory (STM) deficits. He occasionally could not recall even a single syllable that he had heard one second before. A study of mismatch negativity using magnetoencephalography suggested that the duration of auditory sensory (echoic) memory traces was reduced on the affected side of the brain. His maximum digit span was four with auditory presentation (equivalent to the 1st percentile for normal subjects), whereas it was up to six with visual presentation (almost within the normal range). He simply showed partial recall in the digit span task, and there was no self correction or incorrect reproduction. From these findings, reduced echoic memory was thought to have affected his verbal short-term retention. Thus, the impairment of verbal short-term memory observed in this patient was “pure auditory” unlike previously reported patients with deficits of the phonological short-term store (STS), which is the next higher-order memory system. We report this case to present physiological and behavioral data suggesting impaired short-term storage of verbal information, and to demonstrate the influence of deterioration of echoic memory on verbal STM.     

Evaluating short-term and working memory in older adults: French normative data

Short-term and working memory (WM) capacities are subject to change with ageing, both in normal older adults and in patients with degenerative or non-degenerative neurological disease. Few normative data are available for comparisons of short-term and WM capacities in the verbal, spatial and visual domains. To provide researchers and clinicians with a set of standardised tasks that assess short-term and WM using verbal and visuospatial materials, and to present normative data for that set of tasks. The present study compiled normative French data for three short-term memory tasks (verbal, visual and spatial simple span tasks) and two WM tasks (verbal and spatial complex span tasks) obtained from 445 healthy older adults aged between 55 and 85 years. Our data reveal main effects of age, education level and gender on older adults' short-term and WM performances. Equation-based normalisation can therefore be used to take these factors into account. The results provide a set of cut-off scores for five standardised tasks that can be used to determine the presence of short-term or WM impairment in older adults.     

Impaired passive maintenance and spared manipulation of internal representations in patients with schizophrenia

Working memory (WM) impairment is a core feature of schizophrenia (SZ), but the integrity of the various components of WM is unclear. After encoding, mental representations must be maintained in WM during the delay period. In addition to maintenance, manipulation of internal representation can occur in WM. It has been argued that manipulation of items in WM is more impaired than simple maintenance in SZ, but direct empirical data to support this claim have been mixed. Discrepant findings among studies might be explained by task parameters, specifically the degree to which the manipulation task places demands on encoding and maintenance processes. The present study set out to examine these components of WM in patients with SZ (n = 20) and demographically matched healthy controls (n = 19) using a spatial delayed response task (DRT) to measure maintenance processes and 2 mental rotation tasks (allocentric and egocentric) with no delay period or restriction on encoding time to measure manipulation processes. Consistent with previous findings, patients were impaired on the spatial DRT. However, patients performed equally well on the egocentric mental rotation task and were more accurate than controls on the allocentric mental rotation task as the required degree of rotation increased. These results indicated impaired maintenance and spared manipulation of representations in WM and suggest a pocket of cognitive function that might be enhanced in SZ.     

A hemodynamic correlate of lateralized visual short-term memories

Neuroimaging studies attempting to isolate the neural substrate of visual short-term memory in humans have concentrated on the behavior of neurons populating the posterior part of the parietal cortex as a possible source of visual short-term memory capacity limits. Using a standard change-detection task, fMRI studies have shown that maintenance of bilaterally encoded objects elicited bilateral increases of hemodynamic activation in the intra-parietal and intra-occipital sulci (IPS-IOS) proportional to the number of objects retained in visual short-term memory. We used a spatially cued variant of the change-detection task to record hemodynamic responses to unilaterally encoded objects using functional near-infrared spectroscopy (fNIRS). Electrophysiological studies that employed this task have shown that maintenance of unilaterally encoded objects elicited posterior unilateral (contralateral) increase in event-related negativity proportional to the number of objects retained in visual short-term memory. We therefore examined whether contralateral increases in oxy-hemoglobin concentration correlated with the number of retained objects. Contrary to the idea that bilateral increases in BOLD responses and unilateral increases in event-related negativity may be different reflections of the same underlying neural/functional processing, memory-related increases in oxy-hemoglobin concentration were found bilaterally even when objects had to be encoded unilaterally. The present findings suggest that EEG and fMRI/fNIRS techniques reveal distinct neural signatures of the mechanisms supporting visual short-term memory.     

The stability of inhibitory and working memory deficits in children and adolescents who are children of parents with schizophrenia

Cognitive deficits are a central feature of schizophrenia and occur in first-degree relatives of schizophrenic probands, even in the absence of psychotic symptoms. A number of cognitive domains have been implicated including measures of response inhibition and working memory. While the stability of cognitive deficits has been demonstrated in individuals with schizophrenia, stability of deficits has not been explored in first-degree relatives. This report focuses on 25 children (ages 6-15 years), all with at least one schizophrenic parent. The children were assessed twice, utilizing inhibitory and working memory tasks, with a mean 2.6 years between visits. Stop reaction time (a measure of motor inhibition) and performance on a counting span task (a measure of verbal working memory) were borderline to mildly impaired (compared with a typically developing comparison group) at both visits with similar effect sizes (stopping task time 1, effect size = 0.46, time 2 effect size = 0.50; counting span time 1 effect size = 0.53, time 2 effect size = 0.42). For these 2 tasks, individual age-adjusted scores also correlated across both time points (r = 0.41-0.76) suggesting that individual children maintained deficits across time. As etiologically driven strategies are developed for the cognitive deficits of schizophrenia, expansion of these treatments to relatives who share the cognitive but not the psychotic symptoms may be worth exploring.     

Gender differences in the cognitive control of emotion: An fMRI study

The interaction of emotion and cognition has become a topic of major interest. However, the influence of gender on the interplay between the two processes, along with its neural correlates have not been fully analysed so far. In this functional magnetic resonance imaging (fMRI) study we induced negative emotion using negative olfactory stimulation while male (n=21) and female (n=19) participants performed an n-back verbal working memory task. Based on findings indicating increased emotional reactivity in women, we expected the female participants to exhibit stronger activation in characteristically emotion-associated areas during the interaction of emotional and cognitive processing in comparison to the male participants. Both groups were found to be significantly impaired in their working memory performance by negative emotion induction. However, fMRI analysis revealed distinct differences in neuronal activation between groups. In men, cognitive performance under negative emotion induction was associated with extended activation patterns in mainly prefrontal and superior parietal regions. In women, the interaction between emotion and working memory yielded a significantly stronger response in the amygdala and the orbitofrontal cortex (OFC) compared to their male counterparts. Our data suggest that in women the interaction of verbal working memory and negative emotion is associated with relative hyperactivation in more emotion-associated areas whereas in men regions commonly regarded as important for cognition and cognitive control are activated. These results provide new insights in gender-specific cerebral mechanisms.     

Cognitive phenotyping of amyloid precursor protein transgenic J20 mice

Transgenic mice that express familial Alzheimer's disease mutant forms of the human amyloid precursor protein (hAPP) have proved to be invaluable in determining the impact that the neurotoxic amyloid-β peptide has in vivo. In addition to the propensity to accumulate cerebral amyloid plaques, a crucial characteristic of hAPP mouse models is their cognitive impairments. To date the most widely used test for analyzing cognitive impairment in hAPP mice is the Morris water maze (MWM) which, due to the fact that mice are not “natural” swimmers, may not always be the ideal paradigm to investigate cognitive behaviours. Furthermore, not all cognitive impairments have been replicated across research laboratories. In the current study, we characterised the cognitive abilities of the J20 transgenic mouse line (expressing the Swedish 670/671_KM->NL and Indiana (717_V->FhAPP mutations) and non-transgenic mice. Mice were assessed in the cheeseboard task (i.e., a ‘dry version’ of the MWM) and a variety of other cognitive paradigms to test fear conditioning, object recognition and short-term memory to broaden the understanding of the cognitive deficits in J20 mice. hAPP transgenic mice perform normally in tasks for fear conditioning, short-term object recognition and short-term memory of context familiarity. However, they were profoundly impaired in their spatial reference memory capabilities in the cheeseboard task. The cheeseboard task has potential to replace the MWM task in situations where the MWM is not suitable for particular mouse models.     

Differential increase of extracellular dopamine and serotonin in the 'prefrontal cortex' and striatum of pigeons during working memory

Monoamines, such as dopamine (DA) and serotonin (5-HT), play a central role in the modulation of cognitive processes at the forebrain level. Experimental and clinical studies based on dopaminergic pathology, depletion or medication indicate that DA, in particular, is involved in working memory (WM). However, it is unclear whether DA is indeed related to WM, whether its function is specific to the prefrontal cortex (PFC), and whether other modulators, such as 5-HT, might have similar functions. Therefore, the aims of this study were threefold. First, we analysed whether increased prefrontal DA release is related to WM in general or only to its short-term memory component. Second, we examined whether the DA release during cognitive tasks is specific to prefrontal areas or also occurs in the striatum. Third, we analysed whether prefrontal or striatal 5-HT release accompanies working and short-term memory. We approached these questions by using in vivo microdialysis to analyse the extracellular DA and 5-HT release in the pigeons' 'PFC' and striatum during matching-to-sample tasks with or without a delay. Here, we show that DA has no unitary function but is differentially released during working as well as short-term memory in the pigeons' 'prefrontal' cortex. Striatal DA shows an increased efflux only during WM that involves a delay component. WM is also accompanied by a 'prefrontal' but not a striatal release of 5-HT, whose efflux pattern is thus partly different to that of DA. Our findings thus show a triple dissociation between transmitters, structures and tasks within the avian 'prefronto'-striatal system.     

Specific impairments in visuospatial working and short-term memory following low-dose scopolamine challenge in healthy older adults

Scopolamine-induced deficits in cognitive and motor processes have been widely demonstrated in animals and humans, although the role of acetylcholine in working memory is not as well understood. This study examined the role of acetylcholine neurotransmission in visuospatial short term and working memory using the Groton Maze Learning Test (GMLT). The GMLT is a computerized hidden maze learning test that yields measures of component cognitive processes such as spatial memory, working memory, and visuomotor function, as well as their integration in trial-and-error problem solving. Healthy older adults were administered scopolamine (0.3 mg subcutaneous), the acetlycholinesterase inhibitor donepezil (5 mg oral), scopolamine with donepezil, or placebo. Compared to placebo, low-dose scopolamine led to performance deficits on all measures of the GMLT. The greatest scopolamine-induced deficits were observed in errors reflecting working memory processes (e.g., perseverative errors d=-2.98, and rule-break errors d=-2.49) and these impairments remained robust when statistical models accounted for scopolamine-related slowing in visuomotor speed. Co-administration of donepezil partially ameliorated scopolamine-related impairments and this effect was greatest for measures of working memory than short-term memory. By itself, donepezil was associated with a small improvement in visuomotor function. These results suggest that scopolamine disrupts processes required for rule maintenance and performance monitoring, in combination with visuomotor slowing and sequential location learning.