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Mechanisms underlying visual imagery, the ability to create vivid mental representations of a scene in the absence of sensory input, remain to be fully understood. Some previous studies have proposed that visual imagery might be related to visual short-term memory (STM), with a common mechanism involving retention of visual information over short periods of time. Other observations have shown a strong relationship between visual imagery and functional activity in the hippocampus and primary visual cortex, both regions also associated with visual STM. Here we examined the relationship of visual imagery to STM and hippocampal and primary visual cortex volumes, first in a large sample of healthy people across a large age range (N=229 behavioural data; N=56 MRI data in older participants) and then in patients with Alzheimer’s disease and Parkinson’s disease (N=19 in each group compared to 19 age-matched healthy controls). We used a variant of the “What was where?” visual object-location binding task to assess the quality of remembered information over short delays. In healthy people, no evidence of a relationship between the vividness of visual imagery and any visual STM performance parameter was found. However, there was a significant positive correlation between visual imagery and the volumes of the hippocampus and primary visual cortex. Although visual STM performance was significantly impaired in patients with Alzheimer’s disease, their vividness of visual imagery scores were comparable to those of age-matched elderly controls and patients with Parkinson’s disease. Despite hippocampal volumes also being reduced in Alzheimer’s patients, there appeared to be no impact on their self-reported visual imagery. In conclusion, visual imagery was not significantly related to visual STM performance, either in healthy controls or Alzheimer’s or Parkinson’s disease but it was related to hippocampal and visual cortex volume in healthy people.

It has recently been proposed that short-term memory (STM) binding deficits might be an important feature of Alzheimer's disease (AD), providing a potential avenue for earlier detection of this disorder. By contrast, work in Parkinson's disease (PD), using different tasks, has suggested that the STM impairment in this condition is characterised by increased random guessing, possibly due to fluctuating attention. In the present study, to establish whether a misbinding impairment is present in sporadic late-onset AD (LOAD) and increased guessing is a feature of PD, we compared the performance of these patient groups to two control populations: healthy age-matched controls and individuals with subjective cognitive impairment (SCI) with comparable recruitment history as patients. All participants performed a sensitive task of STM that required high resolution retention of object-location bindings. This paradigm also enabled us to explore the underlying sources of error contributing to impaired STM in patients with LOAD and PD using computational modelling of response error. Patients with LOAD performed significantly worse than other groups on this task. Importantly their impaired memory was associated with increased misbinding errors. This was in contrast to patients with PD who made significantly more guessing responses. These findings therefore provide additional support for the presence of two doubly dissociable signatures of STM deficit in AD and PD, with binding impairment in AD and increased random guessing characterising the STM deficit in PD. The task used to measure memory precision here provides an easy-to-administer assessment of STM that is sensitive to the different types of deficit in AD and PD and hence has the potential to inform clinical practice.

Both short- and long-term memories decline with healthy ageing. The aims of the current study were twofold: firstly, to build on previous studies and investigate the presence of a relationship between short- and long-term memories and, secondly, to examine cross-sectionally whether there are changes in this relationship with age. In two experiments, participants across the age range were tested on contextual-spatial memories after short and long memory durations. Experimental control in stimulus materials and task demands enabled the analogous encoding and probing for both memory durations, allowing us to examine the relationship between the two memory systems. Across two experiments, in line with previous studies, we found both short-term memory and long-term memory declined from early to late adulthood. Additionally, there was a significant relationship between short- and long-term memory performance, which, interestingly, persisted throughout the age range. Our findings suggest a significant degree of common vulnerability to healthy ageing for short- and long-term memories sharing the same spatial-contextual associations. Furthermore, our tasks provide a sensitive and promising framework for assessing and comparing memory function at different timescales in disorders with memory deficits at their core.

Neural oscillations are thought to play a central role in orchestrating activity states between distant neural populations. In humans, long-range neural connectivity has been particularly well characterised for 13-30 Hz beta activity which becomes phase coupled between the motor cortex and the contralateral muscle during isometric contraction. Based on this and related observations, beta activity and connectivity have been linked to sustaining stable cognitive and motor states – or the ‘status quo’ – in the brain. Recently, however, beta activity has been shown to be short-lived, as opposed to sustained – though so far this has been reported for regional beta activity in tasks without sustained motor demands. Here, we measured magnetoencephalography (MEG) and electromyography (EMG) in 18 human participants performing an isometric-contraction (gripping) task designed to yield sustained behavioural output. If cortico-muscular beta connectivity is directly responsible for sustaining a stable motor state, then beta activity should be (or become) sustained in this context. In contrast, we found that beta activity and connectivity with the downstream muscle were transient, even when participants engaged in sustained gripping. Moreover, we found that sustained motor requirements did not prolong beta-event duration in comparison to rest. These findings suggest that long-range neural synchronisation may entail short ‘bursts’ of frequency-specific connectivity, even when task demands – and behaviour – are sustained.HighlightsTrial-average 13-30 Hz beta activity and connectivity with the muscle appear sustained during stable motor behaviourSingle-trial beta activity and connectivity are short-lived, even when motor behaviour is sustainedSustained task demands do not prolong beta-event duration in comparison to resting state

Long-range communication through the motor system is thought to be facilitated by phase coupling between neural activity in the 15–30 Hz beta range. During periods of sustained muscle contraction (grip), such coupling is manifest between motor cortex and the contralateral forearm muscles—measured as the cortico-muscular coherence. We examined alterations in cortico-muscular coherence in individuals with Parkinson’s disease, while equating grip strength between individuals with Parkinson’s disease (off their medication) and healthy control participants. We show a marked reduction in beta cortico-muscular coherence in the Parkinson’s disease group, even though the grip strength was comparable between the two groups. Moreover, the reduced cortico-muscular coherence was related to motor symptoms, so that individuals with lower cortico-muscular coherence also displayed worse motor symptoms. These findings highlight the cortico-muscular coherence as a simple, effective and clinically relevant neural marker of Parkinson’s disease pathology, with the potential to aid monitoring of disease progression and the efficacy of novel treatments for Parkinson’s disease., Zokaei et al. report reduced cortico-muscular coherence—coupling between cortex and muscle—in individuals with Parkinson’s disease compared to controls, during well-equated muscle contraction between the two groups. This reduction is related to motor symptoms in patients. This measure can provide a sensitive and objective measure of disease-related motor deficits., Graphical Abstract Graphical Abstract

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.

Background: Cognitive impairment is a very frequent and severe nonmotor symptom of Parkinson’s disease (PD). Early intervention in this at-risk group for cognitive decline may be crucial for long-term preservation of cognitive functions. Computerized working memory training (WMT) has been proven beneficial in non-PD patient populations, but such evidence is still needed for patients with PD. Objective: This study aimed to evaluate the effect of WMT on visuo-spatial working memory (WM) in cognitively unimpaired patients with PD. Methods: A single-blind randomized controlled trial encompassing 76 patients with PD but no cognitive impairment according to level II diagnostic criteria was conducted. Thirty-seven patients engaged in home-based adaptive WMT 5 times per week for a period of 5 weeks, whereas the remaining patients were in the waiting list arm of the study (control group [CG]). Working memory performance was evaluated using a computerized task before and after intervention and at 14-week follow-up, allowing to quantify the precision of WM on a continuous scale, ie, to test not only if an item was remembered but also how well the location of this item was retained. Results: Coincidently, the WMT group showed slightly worse WM performance compared with the CG at baseline, which was ameliorated after WMT. This training-induced effect remained stable until follow-up. Conclusion: Patients showing relatively low WM performance, despite not formally diagnosable as Parkinson’s disease with mild cognitive impairment (PD-MCI), seem to benefit from home-based WMT. Thus, WMT could potentially be implemented in future trials as a time- and cost-efficient route to counteract subtle cognitive changes in early disease stages. Trial registration: German Clinical Trial Register (drks.de, DRKS00009379)

Working memory impairments are frequently observed in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Recent research suggests that the mechanisms underlying these deficits might be dissociable using sensitive tasks, specifically those that rely on the reproduction of the exact quality of features held in memory.In patients with AD, working memory impairments are mainly due to an increase in misbinding errors. They arise when patients misremember which features (e.g., color, orientation, shape, and location) belong to different objects held in memory. Hence, they erroneously report features that belong to items in memory other than the one they are probed on. This misbinding of features that belong to different objects in memory can be considered a form of interference between stored items. Such binding errors are evident even in presymptomatic individuals with familial AD (due to gene mutations) who do not have AD yet. Overall, these findings are in line with the role of the medial temporal lobes, and specifically the hippocampus, in retention of feature bindings, regardless of retention duration, i.e., in both short- or long-term memory.Patients with PD, on the other hand, do not show increased misbinding. Their working memory deficits are associated with making more random errors or guesses. These random responses are not modulated by manipulations of their dopaminergic medication and hence may reflect involvement of non-dopaminergic neurotransmitters in this deficit. In addition, patients with PD demonstrate impairments in gating of information into relevant vs. irrelevant items in memory, a cognitive operation that is modulated by dopaminergic manipulation in line with a frontal executive effect of this neurotransmitter. Thus, although AD and PD are both associated with working memory impairments, these surface manifestations appear to be underpinned by very different mechanisms.

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.

IntroductionPatients with idiopathic RBD have an increased risk of developing a defined neurodegenerative disorder, the majority developing PD. Is it possible to detect features of PD in RBD, before a diagnosis of PD is established?MethodsFifty-seven patients with polysomnography-proven idiopathic RBD and seventy-four control and drug-naïve PD subjects were recruited. All participants underwent a thorough motor and non-motor assessment, and were screened for mutations in glucocerebrosidase (GBA) genes. Visual working memory was separately assessed in 21 RBD, 15 drug-naïve PD and 21 controls using a serial order task testing both recall precision and the pattern of impairment.ResultsRBD patients had increased motor and postural impairment compared to controls. Non-motor deficits (hyposmia, constipation, depression, anxiety) were similar between RBD and PD cases. Furthermore, there was a significant deficit of working memory memory recall precision in PD and RBD, with the pattern of deficit being similar in both groups.ConclusionRBD is associated with motor and non-motor impairment often seen in early PD. The pattern of visual working memory impairment in RBD is equivalent to that observed in early PD. These results support the hypothesis that idiopathic RBD is representative of prodromal sporadic PD.

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.

Embodied theories of cognition propose that neural substrates used in experiencing the referent of a word, for example perceiving upward motion, should be engaged in weaker form when that word, for example 'rise', is comprehended [1-3]. This claim has been broadly supported in the motor domain (for example [4,5]), whilst evidence is supportive, but less clear cut, for perception (for example [6-8]). Motivated by the finding that the perception of irrelevant background motion at near-threshold, but not supra-threshold, levels interferes with task execution [9], we assessed whether interference from near-threshold background motion was modulated by its congruence with the meaning of words (semantic content) when participants completed a lexical decision task (deciding if a string of letters is a real word or not). Reaction times for motion words, such as 'rise' or 'fall', were slower when the direction of visual motion and the 'motion' of the word were incongruent - but only when the visual motion was at near-threshold levels (supporting [9]). When motion was supra-threshold, the distribution of error rates, not reaction times, implicated low-level motion processing in the semantic processing of motion words. As the perception of near-threshold signals is not likely to be influenced by strategies [9], our results support a close contact between semantic information and perceptual systems. © 2008 Elsevier Ltd. All rights reserved.

Studies of selective attention during perception have revealed modulation of the pupillary response according to the brightness of task relevant (attended) vs. irrelevant (unattended) stimuli within a visual display. As a strong test of top-down modulation of the pupil response by selective attention, we asked whether changes in pupil diameter follow internal shifts of attention to memoranda of visual stimuli of different brightness maintained in working memory, in the absence of any visual stimulation. Across three studies, we reveal dilation of the pupil when participants orient attention to the memorandum of a dark grating relative to that of a bright grating. The effect occurs even when the attention-orienting cue is independent of stimulus brightness, and even when stimulus brightness is merely incidental and not required for the working-memory task of judging stimulus orientation. Furthermore, relative dilation and constriction of the pupil occurred dynamically and followed the changing temporal expectation that one or the other stimulus would be probed across the retention delay. The results provide surprising and consistent evidence that pupil responses are under top-down control by cognitive factors even when there is no direct adaptive gain for such modulation, since no visual stimuli were presented or anticipated. The results also strengthen the view of sensory recruitment during working memory, suggesting even activation of sensory receptors. The thought-provoking corollary to our findings is that the pupils provide a reliable measure of what is in the focus of mind, thus giving a different meaning to old proverbs about the eyes being a window to the mind.