Learning to be inflexible: Enhanced attentional biases in Parkinson\u27s disease

Impaired attentional flexibility is considered to be one of the core cognitive deficits in Parkinson\u27s disease (PD). However, the mechanisms that underlie this impairment are contested. Progress in resolving this dispute has also been hindered by the fact that cognitive deficits in PD are heterogeneous; therefore, it is unclear whether attentional impairments are only present in a subgroup of patients. Here, we demonstrate that what differentiates PD patients from age-matched controls is an inability to shift attention away from previously relevant information (perseveration) and an inability to shift attention towards previously irrelevant information (learned irrelevance). In contrast, there was no evidence that PD patients, compared to controls, were impaired in being able to appropriately attend to, or ignore, novel information. Furthermore, when patients were stratified according to their level of executive impairment, the executively impaired group showed a selective deficit in set formation compared to the unimpaired group, a behavioural pattern reminiscent of cortical dopamine depletion. Cumulatively, these results suggest that cognitive inflexibility in PD relates to a specific form of attentional dysfunction, in which learned attentional biases cannot be overcome

Dopamine D2 receptor stimulation modulates the balance between ignoring and updating according to baseline working memory ability

BACKGROUND:Working memory (WM) deficits in neuropsychiatric disorders have often been attributed to altered dopaminergic signalling. Specifically, D2 receptor stimulation is thought to affect the ease with which items can be gated into and out of WM. In addition, this effect has been hypothesised to vary according to baseline WM ability, a putative index of dopamine synthesis levels. Moreover, whether D2 stimulation affects WM vicariously through modulating relatively WM-free cognitive control processes has not been explored. AIMS:We examined the effect of administering a dopamine agonist on the ability to ignore or update information in WM. METHOD:A single dose of cabergoline (1 mg) was administered to healthy older adult humans in a within-subject, double-blind, placebo-controlled study. In addition, we obtained measures of baseline WM ability and relatively WM-free cognitive control (overcoming response conflict). RESULTS:Consistent with predictions, baseline WM ability significantly modulated the effect that drug administration had on the proficiency of ignoring and updating. High-WM individuals were relatively better at ignoring compared to updating after drug administration. Whereas the opposite occurred in low-WM individuals. Although the ability to overcome response conflict was not affected by cabergoline, a negative relationship between the effect the drug had on response conflict performance and ignoring was observed. Thus, both response conflict and ignoring are coupled to dopaminergic stimulation levels. CONCLUSIONS:Cumulatively, these results provide evidence that dopamine affects subcomponents of cognitive control in a diverse, antagonistic fashion and that the direction of these effects is dependent upon baseline WM

Caffeine and attentional control:improved and impaired performance in healthy older adults and Parkinson’s disease according to task demands

INTRODUCTION: Caffeine is frequently consumed to boost goal-directed attention. These procognitive effects may occur due to the adenosine-mediated enhancement of monoamines, such as dopamine, after caffeine administration. As such, caffeine’s beneficial effects may be altered in conditions such as Parkinson’s disease (PD). However, whether caffeine improves cognition, and at what cost, has not been experimentally established in patients with neurodegenerative disease. METHODS: Single-dose trials to probe cognitive effects of caffeine are often confounded by short-term caffeine abstinence which conflates caffeine’s effects with treatment of withdrawal. Using a placebo controlled, blinded, randomised trial design, we assessed the effect of 100 mg of caffeine across well-established tasks (Choice reaction time, Stroop Task and Rapid Serial Visual Presentation Task; RSVP) that probe different aspects of attention in PD patients (n = 24) and controls (n = 44). Critically, participants withdrew from caffeine for a week prior to testing to eliminate the possibility that withdrawal reversal explained any cognitive benefit. RESULTS: Caffeine administration was found to reduce the overall number of errors in patients and controls on the Stroop (p = .018, η(2)(p) = .086) and Choice reaction time (p < . 0001, η(2)(p) = .588) tasks, but there was no specific effect of caffeine on ignoring irrelevant information in the Stroop task. On the RSVP task, caffeine improved dual item accuracy (p = .037) but impaired single item accuracy (p = .044). Across all tasks, there was little evidence that caffeine has different effects in PD participants and controls. CONCLUSION: When removing withdrawal effects as a factor, we demonstrate caffeine has beneficial effects on selective attention but is a double-edge sword for visual temporal attention and would need careful targeting to be clinically useful. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-021-06054-9

Dopamine affects short-term memory corruption over time in Parkinson’s disease

Cognitive deficits are a recognised component of Parkinson’s disease (PD). However, particularly within the domain of short-term memory, it is unclear whether these impairments are masked, or caused, by patients’ dopaminergic medication. The effect of medication on pure maintenance in PD patients has rarely been explored, with most assessments examining maintenance intercalated between other executive tasks. Moreover, few studies have utilised methods that can measure the quality of mental representations, which can enable the decomposition of recall errors into their underlying neurocognitive components. Here, we fill this gap by examining pure maintenance in PD patients in high and low dopaminergic states. Participants had to encode the orientation of two stimuli and reproduce these orientations after a short (2 s) or long (8 s) delay. In addition, we also examined the performance of healthy, age-matched older adults to contextualise these effects and determine whether PD represents an exacerbation of the normal ageing process. Patients showed improved recall OFF compared to ON their dopaminergic medication, but only for long-duration trials. Moreover, PD patients OFF their medication actually performed at a level superior to age-matched controls, indicative of a paradoxical enhancement of memory in the low dopaminergic state. The application of a probabilistic model of response selection suggested that PD patients made fewer misbinding errors in the low, compared with high, dopaminergic state for longer-delay trials. Thus, unexpectedly, the mechanisms that prevent memoranda from being corrupted by misbinding over time appear to be enhanced in PD patients OFF dopaminergic medication. Possible explanations for this paradoxical effect are discussed

Effects of cholinesterase inhibition on attention and working memory in Lewy body dementias

Cholinesterase inhibitors are frequently used to treat cognitive symptoms in Lewy body dementias (Parkinson’s disease dementia and Dementia with Lewy bodies). However, the selectivity of their effects remains unclear. In a novel rivastigmine-withdrawal design, Parkinson’s disease dementia and Dementia with Lewy bodies patients were tested twice: once when taking rivastigmine as usual and once when they had missed one dose. In each session, they performed a suite of tasks (sustained attention, simple short-term recall, distractor resistance and manipulating the focus of attention) which allowed us to investigate the cognitive mechanisms through which rivastigmine affects attentional control. Consistent with previous literature, rivastigmine withdrawal significantly impaired attentional efficacy (quicker response latencies without a change in accuracy). However, it had no effects on cognitive control as assessed by the ability to withhold a response (inhibitory control). Worse short-term memory performance was also observed when patients were OFF rivastigmine, but these effects were delay and load-independent, likely due to impaired visual attention. In contrast to previous studies that have examined the effects of dopamine withdrawal, cognitively complex tasks requiring control over the contents of working memory (ignoring, updating or shifting the focus of attention) were not significantly impaired by rivastigmine withdrawal. Cumulatively, these data support the conclusion cholinesterase inhibition has relatively specific and circumscribed – rather than global – effects on attention that may also affect performance on simple short-term memory tasks, but not when cognitive control over working memory is required. The results also indicate that withdrawal of a single dose of rivastigmine is sufficient to reveal these impairments, demonstrating that cholinergic withdrawal can be an informative clinical as well as an investigative tool

Task-irrelevant financial losses inhibit the removal of information from working memory

Abstract The receipt of financial rewards or penalties - though task-irrelevant - may exert an obligatory effect on manipulating items in working memory (WM) by constraining a forthcoming shift in attention or reinforcing attentional shifts that have previously occurred. Here, we adjudicate between these two hypotheses by varying – after encoding- the order in which task-irrelevant financial outcomes and cues indicating which items need to be retained in memory are presented (so called retrocues). We employed a “what-is-where” design that allowed for the fractionation of WM recall into separate components: identification, precision and binding (between location and identity). Principally, valence-dependent effects were observed only for precision and binding, but only when outcomes were presented before, rather than after, the retrocue. Specifically, task-irrelevant financial losses presented before the retrocue caused a systematic breakdown in binding (misbinding), whereby the features of cued and non-cued memoranda became confused, i.e., the features that made up relevant memoranda were displaced by those of non-cued (irrelevant) items. A control experiment, in which outcomes but no cues were presented, failed to produce the same effects, indicating that the inclusion of retrocues were necessary for generating this effect. These results show that the receipt of financial penalties – even when uncoupled to performance – can prevent irrelevant information from being effectively pruned from WM. These results illustrate the importance of reward-related processing to controlling the contents of WM

Dopamine guides competition for cognitive control:Common effects of haloperidol on working memory and response conflict

Several lines of evidence suggest that dopamine modulates working memory (the ability to faithfully maintain and efficiently manipulate information over time) but its specific role has not been fully defined. Nor is it clear whether any effects of dopamine are specific to memory processes or whether they reflect more general cognitive mechanisms that extend beyond the working memory domain. Here, we examine the effect of haloperidol, principally a dopamine D2 receptor antagonist, on the ability of humans to ignore distracting information or update working memory contents. We compare these effects to performance on an independent measure of cognitive control (response conflict) which has minimal memory requirements. Haloperidol did not selectively affect the ability to ignore or update, but instead reduced the overall quality of recall. In addition, it impaired the ability to overcome response conflict. The deleterious effect of haloperidol on response conflict was selectively associated with the negative effect of the drug on ignoring - but not updating - suggesting that dopamine affects protection of working memory contents and inhibition in response conflict through a common mechanism. These findings provide new insights into the role of dopamine D2 receptors on human cognition. They suggest that D2 receptor effects on protecting the memory contents from distraction might be related to a more general process that supports inhibitory control in contexts that do not require working memory

T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls (n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships

Retraction Notice to: Suppressors of Cytokine Signaling 2 and 3 Diametrically Control Macrophage Polarization

Friday, 8th December 1916