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The Apolipoprotein-E (APOE) ε4 gene allele, the highest known genetic risk factor for Alzheimer’s disease, has paradoxically been well preserved in the human population. One possible explanation offered by evolutionary biology for survival of deleterious genes is antagonistic pleiotropy. This theory proposes that such genetic variants might confer an advantage, even earlier in life when humans are also reproductively fit. The results of some small-cohort studies have raised the possibility of such a pleiotropic effect for the ε4 allele in short-term memory (STM) but the findings have been inconsistent. Here, we tested STM performance in a large cohort of individuals (N = 1277); nine hundred and fifty-nine of which included carrier and non-carriers of the APOE ε4 gene, those at highest risk of developing Alzheimer’s disease. We first confirm that this task is sensitive to subtle deterioration in memory performance across ageing. Importantly, individuals carrying the APOE ε4 gene actually exhibited a significant memory advantage across all ages, specifically for brief retention periods but crucially not for longer durations. Together, these findings present the strongest evidence to date for a gene having an antagonistic pleiotropy effect on human cognitive function across a wide age range, and hence provide an explanation for the survival of the APOE ε4 allele in the gene pool.

Aging adults typically show reduced ability to ignore task-irrelevant information, an essential skill for optimal performance in many cognitive operations, including those requiring working memory (WM) resources. In a first experiment, young and elderly human participants of both genders performed an established WM paradigm probing inhibitory abilities by means of valid, invalid, and neutral retro-cues. Elderly participants showed an overall cost, especially in performing invalid trials, whereas younger participants' general performance was comparatively higher, as expected.Inhibitory abilities have been linked to alpha brain oscillations but it is yet unknown whether in aging these oscillations (also typically impoverished) and inhibitory abilities are causally linked. To probe this possible causal link in aging, we compared in a second experiment parietal alpha-transcranial alternating current stimulation (tACS) with either no stimulation (Sham) or with two control stimulation frequencies (theta- and gamma-tACS) in the elderly group while performing the same WM paradigm. Alpha- (but not theta- or gamma-) tACS selectively and significantly improved performance (now comparable to younger adults' performance in the first experiment), particularly for invalid cues where initially elderly showed the highest costs. Alpha oscillations are therefore causally linked to inhibitory abilities and frequency-tuned alpha-tACS interventions can selectively change these abilities in the elderly.SIGNIFICANCE STATEMENTIgnoring task-irrelevant information, an ability associated to rhythmic brain activity in the alpha frequency band, is fundamental for optimal performance. Indeed, impoverished inhibitory abilities contribute to age-related decline in cognitive functions like working memory (WM), the capacity to briefly hold information in mind. Whether in aging adults alpha oscillations and inhibitory abilities arecausallylinked is yet unknown. We experimentally manipulated frequency-tuned brain activity using transcranial alternating current stimulation (tACS), combined with a retro-cue paradigm assessing WM and inhibition. We found that alpha-tACS induced a significant improvement in target responses and misbinding errors, two indexes of inhibition. We concluded that in aging alpha oscillations are causally linked to inhibitory abilities, and that despite being impoverished, these abilities are still malleable.

Studying the sources of errors in memory recall has proven invaluable for understanding the mechanisms of working memory (WM). While one-dimensional memory features (e.g., color, orientation) can be analyzed using existing mixture modeling toolboxes to separate the influence of imprecision, guessing, and misbinding (the tendency to confuse features that belong to different memoranda), such toolboxes are not currently available for two-dimensional spatial WM tasks.Here we present a method to isolate sources of spatial error in tasks where participants have to report the spatial location of an item in memory, using two-dimensional mixture models. The method recovers simulated parameters well and is robust to the influence of response distributions and biases, as well as number of nontargets and trials.To demonstrate the model, we fit data from a complex spatial WM task and show the recovered parameters correspond well with previous spatial WM findings and with recovered parameters on a one-dimensional analogue of this task, suggesting convergent validity for this two-dimensional modeling approach. Because the extra dimension allows greater separation of memoranda and responses, spatial tasks turn out to be much better for separating misbinding from imprecision and guessing than one-dimensional tasks.Code for these models is freely available in the MemToolbox2D package and is integrated to work with the commonly used MATLAB package MemToolbox.

Classical views of the medial temporal lobe (MTL) have established that it plays a crucial role in long‐term memory (LTM). Here we demonstrate, in a sample of patients who have undergone anterior temporal lobectomy for the treatment of pharmacoresistant epilepsy, that the MTL additionally plays a specific, causal role in short‐term memory (STM). Patients (n=22) and age‐matched healthy control participants (n=26) performed a STM task with a sensitive continuous report measure. This paradigm allowed us to examine recall memory for object identity, location and object‐location binding, independently on a trial‐by‐trial basis. Our findings point to a specific involvement of MTL in object‐location binding, but, crucially, not retention of either object identity or location. Therefore the MTL appears to perform a specific computation: binding disparate features that belong to a memory. These results echo findings from previous studies, which have identified a role for the MTL in relational binding for LTM, and support the proposal that MTL regions perform such a function for both STM and LTM, independent of the retention duration. Furthermore, these findings and the methodology employed here may provide a simple, sensitive and clinically valuable means to test memory dysfunuction in MTL disorders.

Delayed adjustment tasks have recently been developed to examine working memory (WM) precision, that is, the resolution with which items maintained in memory are recalled. However, despite their emerging use in experimental studies of healthy people, evaluation of patient populations is sparse. We first investigated the validity of adjustment tasks, comparing precision with classical span measures of memory across the lifespan in 114 people. Second, we asked whether precision measures can potentially provide a more sensitive measure of WM than traditional span measures. Specifically, we tested this hypothesis examining WM in a group with early, untreated Parkinson's disease (PD) and its modulation by subsequent treatment on dopaminergic medication. Span measures correlated with precision across the lifespan: in children, young, and elderly participants. However, they failed to detect changes in WM in PD patients, either pre- or post-treatment initiation. By contrast, recall precision was sensitive enough to pick up such changes. PD patients pre-medication were significantly impaired compared to controls, but improved significantly after 3 months of being established on dopaminergic medication. These findings suggest that precision methods might provide a sensitive means to investigate WM and its modulation by interventions in clinical populations.

Capacity limitations in working memory (WM) necessitate the need to effectively control its contents. Here, we examined the effect of cabergoline, a dopamine D2 receptor agonist, on WM using a continuous report paradigm that allowed us to assess the fidelity with which items are stored. We assessed recall performance under three different gating conditions: remembering only one item, being cued to remember one target among distractors, and having to remember all items. Cabergoline had differential effects on recall performance according to whether distractors had to be ignored and whether mnemonic resources could be deployed exclusively to the target. Compared with placebo, cabergoline improved mnemonic performance when there were no distractors but significantly reduced performance when distractors were presented in a precue condition. No significant difference in performance was observed under cabergoline when all items had to be remembered. By applying a stochastic model of response selection, we established that the causes of drug-induced changes in performance were due to changes in the precision with which items were stored in WM. However, there was no change in the extent to which distractors were mistaken for targets. Thus, D2 agonism causes changes in the fidelity of mnemonic representations without altering interference between memoranda.

Recent studies investigating working memory for location, color, and orientation support a dynamic resource model. We examined whether this might also apply to motion, using random dot kinematograms (RDKs) presented sequentially or simultaneously. Mean precision for motion direction declined as sequence length increased, with precision being lower for earlier RDKs. Two alternative models of working memory were compared specifically to distinguish between the contributions of different sources of error that corrupt memory (W. Zhang and S. J. Luck, 2008 vs. P. M. Bays, R. F. G. Catalao, and M. Husain, 2009). The latter provided a significantly better fit for the data, revealing that decrease in memory precision for earlier items is explained by an increase in interference from other items in a sequence rather than random guessing or a temporal decay of information. Misbinding feature attributes is an important source of error in working memory. Precision of memory for motion direction decreased when two RDKs were presented simultaneously as transparent surfaces, compared to sequential RDKs. However, precision was enhanced when one motion surface was prioritized, demonstrating that selective attention can improve recall precision. These results are consistent with a resource model that can be used as a general conceptual framework for understanding working memory across a range of visual features. © ARVO.

Visual working memory (VWM) is the facility to hold in mind visual information for brief periods of time. Developmental studies have suggested an increase during childhood in the maximum number of complete items that can simultaneously be stored in VWM. Here, we exploit a recent theoretical and empirical innovation to investigate instead the precision with which items are stored in VWM, where precision is a continuous measure reflecting VWM resolution. Ninety boys aged 7 to 13years completed one-item and three-item VWM tasks in which stimuli were coloured bars varying in orientation. On each trial, participants used a rotating dial to reproduce the probed stimulus from memory. Results show linear age-related improvement in recall precision for both one-item and three-item VWM tasks. However, even the youngest age group stored a significant amount of information about all three items on the difficult 3-item VWM task. Importantly, the development of VWM precision was not accounted for by development on a sensorimotor control task. Whereas storage of a single complete item was previously thought to be well within the capacity limitations of the current age range, these results suggest protracted development during childhood and early adolescence in the resolution with which single and multiple items are stored in VWM. Probabilistic modelling of response distribution data suggests that improvement in VWM performance is attributable to a specific decrease in variability of stored feature representations, rather than to a decrease in misbinding or random noise. As such, we highlight a novel, potentially developmentally plausible mechanism that may underlie developmental improvement in VWM performance, independent of any alterations in the maximum number of complete items which can be stored. © 2012 Blackwell Publishing Ltd.

Individuals with REM sleep behaviour disorder are at significantly higher risk of developing Parkinson's disease. Here we examined visual short-term memory deficits--long associated with Parkinson's disease--in patients with REM sleep behaviour disorder without Parkinson's disease using a novel task that measures recall precision. Visual short-term memory for sequentially presented coloured bars of different orientation was assessed in 21 patients with polysomnography-proven idiopathic REM sleep behaviour disorder, 26 cases with early Parkinson's disease and 26 healthy controls. Three tasks using the same stimuli controlled for attentional filtering ability, sensorimotor and temporal decay factors. Both patients with REM sleep behaviour disorder and Parkinson's disease demonstrated a deficit in visual short-term memory, with recall precision significantly worse than in healthy controls with no deficit observed in any of the control tasks. Importantly, the pattern of memory deficit in both patient groups was specifically explained by an increase in random responses. These results demonstrate that it is possible to detect the signature of memory impairment associated with Parkinson's disease in individuals with REM sleep behaviour disorder, a condition associated with a high risk of developing Parkinson's disease. The pattern of visual short-term memory deficit potentially provides a cognitive marker of 'prodromal' Parkinson's disease that might be useful in tracking disease progression and for disease-modifying intervention trials.

Emerging evidence suggests that items held in working memory (WM) might not all be in the same representational state. One item might be privileged over others, making it more accessible and thereby recalled with greater precision. Here, using transcranial magnetic stimulation (TMS), we provide causal evidence in human participants that items in WM are differentially susceptible to disruptive TMS, depending on their state, determined either by task relevance or serial position. Across two experiments, we applied TMS to area MT+ during the WM retention of two motion directions. In Experiment 1, we used an “incidental cue” to bring one of the two targets into a privileged state. In Experiment 2, we presented the targets sequentially so that the last item was in a privileged state by virtue of recency. In both experiments, recall precision of motion direction was differentially affected by TMS, depending on the state of the memory target at the time of disruption. Privileged items were recalled with less precision, whereas nonprivileged items were recalled with higher precision. Thus, only the privileged item was susceptible to disruptive TMS over MT+. By contrast, precision of the nonprivileged item improved either directly because of facilitation by TMS or indirectly through reduced interference from the privileged item. Our results provide a unique line of evidence, as revealed by TMS over a posterior sensory brain region, for at least two different states of item representation in WM.

Working memory and attention are intimately connected. However, understanding the relationship between the two is challenging. Currently, there is an important controversy about whether objects in working memory are maintained automatically or require resources that are also deployed for visual or auditory attention. Here we investigated the effects of loading attention resources on precision of visual working memory, specifically on correct maintenance of feature-bound objects, using a dual-task paradigm. Participants were presented with a memory array and were asked to remember either direction of motion of random dot kinematograms of different colour, or orientation of coloured bars. During the maintenance period, they performed a secondary visual or auditory task, with varying levels of load. Following a retention period, they adjusted a coloured probe to match either the motion direction or orientation of stimuli with the same colour in the memory array. This allowed us to examine the effects of an attention-demanding task performed during maintenance on precision of recall on the concurrent working memory task. Systematic increase in attention load during maintenance resulted in a significant decrease in overall working memory performance. Changes in overall performance were specifically accompanied by an increase in feature misbinding errors: erroneous reporting of nontarget motion or orientation. Thus in trials where attention resources were taxed, participants were more likely to respond with nontarget values rather than simply making random responses. Our findings suggest that resources used during attention-demanding visual or auditory tasks also contribute to maintaining feature-bound representations in visual working memory—but not necessarily other aspects of working memory.

Predictions from perceptual load theory (Lavie, 1995, 2005) regarding object recognition across the same or different viewpoints were tested. Results showed that high perceptual load reduces distracter recognition levels despite always presenting distracter objects from the same view. They also showed that the levels of distracter recognition were unaffected by a change in the distracter object view under conditions of low perceptual load. These results were found both with repetition priming measures of distracter recognition and with performance on a surprise recognition memory test. The results support load theory proposals that distracter recognition critically depends on the level of perceptual load. The implications for the role of attention in object recognition theories are discussed.

In this study, we investigated the effects of tDCS over the posterior parietal cortex (PPC) during a visual working memory (WM) task, which probes different sources of response error underlying the precision of WM recall. In two separate experiments, we demonstrated that tDCS enhanced WM precision when applied bilaterally over the PPC, independent of electrode configuration. In a third experiment, we demonstrated with unilateral electrode configuration over the right PPC, that only cathodal tDCS enhanced WM precision and only when baseline performance was low. Looking at the effects on underlying sources of error, we found that cathodal stimulation enhanced the probability of correct target response across all participants by reducing feature-misbinding. Only for low-baseline performers, cathodal stimulation also reduced variability of recall. We conclude that cathodal- but not anodal tDCS can improve WM precision by preventing feature-misbinding and hereby enhancing attentional selection. For low-baseline performers, cathodal tDCS also protects the memory trace. Furthermore, stimulation over bilateral PPC is more potent than unilateral cathodal tDCS in enhancing general WM precision., Highlights • Despite multiple studies, reported effects of tDCS on cognitive processes have remained variable. • We employ a WM task that probes different underlying sources of error to test effect of tDCS separately. • tDCS applied bilaterally to the PPC boosts WM precision. • Unilateral stimulation indicates this is caused by cathodal- rather than anodal stimulation. • Improvement relies particularly on enhanced selective attention as well as memory trace protection.