N-methyl-D-aspartate receptor- antibody encephalitis impairs maintenance of attention to items in working memory.

NMDA receptors (NMDAR) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information respectively. We test this in patients with antibodies to NMDAR (n=10, female) and compare them with healthy control participants (n=55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue), or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays (Group x Congruency [long condition], p=0.041), indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues (Group x Delay [congruent condition], main effect of group, p=<0.001). Our results suggest NMDARs are critical for both maintaining attention and feature binding.Significance Statement Computational theories suggest NMDA receptors (NMDARs) are critical for actively maintaining information, while other theories propose they allow us to associate or "bind" objects features together. This is the first causal test in humans of the role of NMDARs in actively maintaining attention in working memory and feature binding. We find patients have difficulty with both these processes in support of computational models. Notably, we demonstrate that patients with NMDA receptor-antibody encephalitis are an ideal model condition to study roles of receptors in human cognition. Secondly, few studies follow these patients long after treatment. Our findings demonstrate a specific long-term neuropsychological deficit, previously unreported to our knowledge, that highlights the need for greater focus on neurocognitive rehabilitation with these patients.

Motivation improves working memory by two processes: Prioritisation and retrieval thresholds.

Motivation can improve performance when the potential rewards outweigh the cost of effort expended. In working memory (WM), people can prioritise rewarded items at the expense of unrewarded items, suggesting a fixed memory capacity. But can capacity itself change with motivation? Across four experiments (N = 30-34) we demonstrate motivational improvements in WM even when all items were rewarded. However, this was not due to better memory precision, but rather better selection of the probed item within memory. Motivational improvements operated independently of encoding, maintenance, or attention shifts between items in memory. Moreover, motivation slowed responses. This contrasted with the benefits of rewarding items unequally, which allowed prioritisation of one item over another. We conclude that motivation can improve memory recall, not via precision or capacity, but via speed-accuracy trade-offs when selecting the item to retrieve.

A new toolbox to distinguish the sources of spatial memory error.

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.

Dopamine and Consolidation of Episodic Memory: Timing is Everything.

Memory consolidation underpins adaptive behavior and dopaminergic networks may be critical for prolonged, selective information storage. To understand the time course of the dopaminergic contribution to memory consolidation in humans, here we investigate the effect of dopaminergic medication on recall and recognition in the short and longer term in Parkinson disease (PD). Fifteen people with PD were each tested on or off dopaminergic medication during learning/early consolidation (Day 1) and/or late consolidation (Day 2). Fifteen age-matched healthy participants were tested only once. On Day 1 participants learned new information, and early episodic memory was tested after 30 min. Then on Day 2, recall and recognition were retested after a 24-hr delay. Participants on medication on Day 1 recalled less information at 30 min and 24 hr. In contrast, patients on medication on Day 2 (8-24 hr after learning) recalled more information at 24 hr than those off medication. Although recognition sensitivity was unaffected by medication, response bias was dependent on dopaminergic state: Medication during learning induced a more liberal bias 24 hr later, whereas patients off medication during learning were more conservative responders 24 hr later. We use computational modeling to propose possible mechanisms for this change in response bias. In summary, dopaminergic medication in PD patients during learning impairs early consolidation of episodic memory and makes delayed responses more liberal, but enhances late memory consolidation presumably through a dopamine-dependent consolidation pathway that may be active during sleep.

Relational Work Is the Work: Virtual Healthcare Transformation for Rural, Remote and First Nations Communities in British Columbia.

The healthcare crisis across unceded First Nations' territories in rural, remote and Indigenous communities in British Columbia (BC) is marked by persistent barriers to accessing care and support close to home. This commentary describes an exceptional story of how technology, trusted partnerships and relationships came together to create an innovative suite of virtual care programs called "Real-Time Virtual Support" (RTVS). We describe key approaches, learnings and future considerations to improve the equity of healthcare delivery for rural, remote and First Nations communities. The key lessons include the following: (1) moving beyond a biomedical model - the collaboration framework for health service design incorporated First Nations' perspective on health and wellness; (2) relational work is the work - the RTVS collaboration was grounded in building connections and relationships to prioritize cultivating trust in the partnership over specific outputs; and (3) aligning to the core values of co-creation - working from a commitment to do things differently and applying an inclusive approach of engagement to integrate perspectives across different sectors and interest groups.

Confidence is predicted by pre- and post-choice decision signal dynamics.

It is well established that one's confidence in a choice can be influenced by new evidence encountered after commitment has been reached, but the processes through which post-choice evidence is sampled remain unclear. To investigate this, we traced the pre- and post-choice dynamics of electrophysiological signatures of evidence accumulation (Centro-parietal Positivity, CPP) and motor preparation (mu/beta band) to determine their sensitivity to participants' confidence in their perceptual discriminations. Pre-choice CPP amplitudes scaled with confidence both when confidence was reported simultaneously with choice, and when reported 1 second after the initial direction decision with no intervening evidence. When additional evidence was presented during the post-choice delay period, the CPP exhibited sustained activation after the initial choice, with a more prolonged build-up on trials with lower certainty in the alternative that was finally endorsed, irrespective of whether this entailed a change-of-mind from the initial choice or not. Further investigation established that this pattern was accompanied by later lateralisation of motor preparation signals toward the ultimately chosen response and slower confidence reports when participants indicated low certainty in this response. These observations are consistent with certainty-dependent stopping theories according to which post-choice evidence accumulation ceases when a criterion level of certainty in a choice alternative has been reached, but continues otherwise. Our findings have implications for current models of choice confidence, and predictions they may make about EEG signatures.

L-DOPA increases slow-wave sleep duration and selectively modulates memory persistence in older adults.

Introduction: Millions of people worldwide take medications such as L-DOPA that increase dopamine to treat Parkinson's disease. Yet, we do not fully understand how L-DOPA affects sleep and memory. Our earlier research in Parkinson's disease revealed that the timing of L-DOPA relative to sleep affects dopamine's impact on long-term memory. Dopamine projections between the midbrain and hippocampus potentially support memory processes during slow wave sleep. In this study, we aimed to test the hypothesis that L-DOPA enhances memory consolidation by modulating NREM sleep. Methods: We conducted a double-blind, randomised, placebo-controlled crossover trial with healthy older adults (65-79 years, n = 35). Participants first learned a word list and were then administered long-acting L-DOPA (or placebo) before a full night of sleep. Before sleeping, a proportion of the words were re-exposed using a recognition test to strengthen memory. L-DOPA was active during sleep and the practice-recognition test, but not during initial learning. Results: The single dose of L-DOPA increased total slow-wave sleep duration by approximately 11% compared to placebo, while also increasing spindle amplitudes around slow oscillation peaks and around 1-4 Hz NREM spectral power. However, behaviourally, L-DOPA worsened memory of words presented only once compared to re-exposed words. The coupling of spindles to slow oscillation peaks correlated with these differential effects on weaker and stronger memories. To gauge whether L-DOPA affects encoding or retrieval of information in addition to consolidation, we conducted a second experiment targeting L-DOPA only to initial encoding or retrieval and found no behavioural effects. Discussion: Our results demonstrate that L-DOPA augments slow wave sleep in elderly, perhaps tuning coordinated network activity and impacting the selection of information for long-term storage. The pharmaceutical modification of slow-wave sleep and long-term memory may have clinical implications. Clinical trial registration: Eudract number: 2015-002027-26; https://doi.org/10.1186/ISRCTN90897064, ISRCTN90897064.

Dissociable effects of APOE-ε4 and ß-amyloid pathology on visual working memory.

Although APOE-ε4 carriers are at significantly higher risk of developing Alzheimer's disease than non-carriers1, controversial evidence suggests that APOE-ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of APOE-ε4 and ß-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, APOE-ε4 and ß-amyloid had opposing effects on object identification, predicting better and poorer recall respectively. ε4-carriers also recalled locations more precisely, with a greater advantage at higher ß-amyloid burden. These results provide evidence of superior visual working memory in ε4-carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer's disease.

Dopamine promotes instrumental motivation, but reduces reward-related vigour.

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinson's disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity residuals) for contingent rewards, whereas when PD patients were OFF medication, they had greater vigour for guaranteed rewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine promotes goal-directed motivation, but dampens reward-driven vigour, contradictory to the prediction that increased tonic dopamine amplifies reward expectation.

Comparison of conventional and rapid-acting antidepressants in a rodent probabilistic reversal learning task.

Deficits in reward processing are a central feature of major depressive disorder with patients exhibiting decreased reward learning and altered feedback sensitivity in probabilistic reversal learning tasks. Methods to quantify probabilistic learning in both rodents and humans have been developed, providing translational paradigms for depression research. We have utilised a probabilistic reversal learning task to investigate potential differences between conventional and rapid-acting antidepressants on reward learning and feedback sensitivity. We trained 12 rats in a touchscreen probabilistic reversal learning task before investigating the effect of acute administration of citalopram, venlafaxine, reboxetine, ketamine or scopolamine. Data were also analysed using a Q-learning reinforcement learning model to understand the effects of antidepressant treatment on underlying reward processing parameters. Citalopram administration decreased trials taken to learn the first rule and increased win-stay probability. Reboxetine decreased win-stay behaviour while also decreasing the number of rule changes animals performed in a session. Venlafaxine had no effect. Ketamine and scopolamine both decreased win-stay probability, number of rule changes performed and motivation in the task. Insights from the reinforcement learning model suggested that reboxetine led animals to choose a less optimal strategy, while ketamine decreased the model-free learning rate. These results suggest that reward learning and feedback sensitivity are not differentially modulated by conventional and rapid-acting antidepressant treatment in the probabilistic reversal learning task.

Short-term memory advantage for brief durations in human APOE ε4 carriers.

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.

Effects of Parkinson's disease and dopamine on digit span measures of working memory.

RATIONALE: Parkinson's disease (PD) impairs working memory (WM)-the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes. OBJECTIVES: We hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults. METHODS: We tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards, and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively. RESULTS: PD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards). CONCLUSIONS: This suggests that the deficit of maintenance capacity and manipulation accuracy in PD patients is not primarily a dopaminergic one and supports a potential "overdosing" of intact manipulation mechanisms in healthy older adults by levodopa.

Effects of dopamine on reinforcement learning and consolidation in Parkinson's disease.

Emerging evidence suggests that dopamine may modulate learning and memory with important implications for understanding the neurobiology of memory and future therapeutic targeting. An influential hypothesis posits that dopamine biases reinforcement learning. More recent data also suggest an influence during both consolidation and retrieval. Eighteen Parkinson's disease patients learned through feedback ON or OFF medication, with memory tested 24 hr later ON or OFF medication (4 conditions, within-subjects design with matched healthy control group). Patients OFF medication during learning decreased in memory accuracy over the following 24 hr. In contrast to previous studies, however, dopaminergic medication during learning and testing did not affect expression of positive or negative reinforcement. Two further experiments were run without the 24 hr delay, but they too failed to reproduce effects of dopaminergic medication on reinforcement learning. While supportive of a dopaminergic role in consolidation, this study failed to replicate previous findings on reinforcement learning.

Paced reading in semantic dementia: word knowledge contributes to phoneme binding in rapid speech production.

Patients with semantic dementia (SD) show deficits in phoneme binding in immediate serial recall: when attempting to reproduce a sequence of words that they no longer fully understand, they show frequent migrations of phonemes between items (e.g., cap, frog recalled as "frap, cog"). This suggests that verbal short-term memory emerges directly from interactions between semantic and phonological systems, allowing semantic knowledge to make a critical contribution to the stability of phonological sequences. According to this standpoint, SD patients should show phoneme binding deficits in additional language tasks beyond standard assessments of verbal short-term memory: for example, these errors should emerge in paced reading, which also requires the rapid production of semantically degraded words in order. To test this hypothesis, we examined a cyclical paced reading task in three SD patients for the first time. Every patient showed deficits in phoneme binding: they were more vulnerable than a set of age-matched controls to phoneme competition effects following the repetition of a small set of words across several cycles. They also showed substantially elevated numbers of phoneme migration, substitution and omission errors, despite being able to read the individual words almost without error. These findings confirm that the semantic contribution to phoneme binding is disrupted in SD patients across tasks. In line with the view that verbal short-term memory emerges from interactions between basic phonological and semantic components, these effects occur both within classic short-term memory paradigms, such as immediate serial recall, and tasks without explicit memory demands, such as paced reading.

Diesel particulate matter exposure to railroad train crews.

Exposure assessments were conducted aboard diesel locomotives. Results were evaluated to determine variables that affect exposure to DPM (diesel particulate matter) and to assess use of EC (elemental carbon) and OC (organic carbon) as surrogates for DPM. National Institute for Occupational Safety and Health Method 5040 was used for collection and analysis of samples in locomotives and in nonrailroad settings. The level of EC, but not OC, in locomotives was found to be significantly affected by position of exhaust stacks and windows. EC ranged from < 1 to 45 micrograms/m3 with a geometric mean (GM) of 3.7 micrograms/m3 and OC ranged from 4 to 4570 micrograms/m3 with a GM of 36.3 micrograms/m3. Background measurements of EC ranged from < 1 to 8 micrograms/m3 and OC levels were 4 to 84 micrograms/m3. This study confirms that train crew exposure to DPM is much lower than exposures for miners, is comparable to background urban exposures, and is lower than but comparable to exposures for truck drivers. It also indicates that EC levels are highly predictive of diesel exhaust exposure whereas OC levels are not, and that open windows and exhaust stack(s) in front of the locomotive cab have a significant effect on EC.