Mechanisms underlying corruption of working memory in Parkinson's disease.

Working memory (WM) impairments are reported to occur in patients with Parkinson's disease (PD). However, the mechanisms are unclear. Here, we investigate several putative factors that might drive poor performance, by examining the precision of recall, the order in which items are recalled and whether memories are corrupted by random guessing (attentional lapses). We used two separate tasks that examined the quality of WM recall under different loads and retention periods, as well as a traditional digit span test. Firstly, on a simple measure of WM recall, where patients were asked to reproduce the orientation of a centrally presented arrow, overall recall was not significantly impaired. However, there was some evidence for increased guessing (attentional lapses). On a new analogue version of the Corsi-span task, where participants had to reproduce on a touchscreen the exact spatial pattern of presented stimuli in the order and locations in which they appeared, there was a reduction in the precision of spatial WM at higher loads. This deficit was due to misremembering item order. At the highest load, there was reduced recall precision, whereas increased guessing was only observed at intermediate set sizes. Finally, PD patients had impaired backward, but not forward, digit spans. Overall, these results reveal the task- and load-dependent nature of WM deficits in PD. On simple low-load tasks, attentional lapses predominate, whereas at higher loads, in the spatial domain, the corruption of mnemonic information-both order item and precision-emerge as the main driver of impairment.

Role of serotonin in modulation of decision-making in Parkinson's disease.

BACKGROUND: Dysfunction of dopaminergic pathways has been considered to play a pivotal role in Parkinson's disease (PD), affecting the processing of emotional and rewarding information, and potentially leading to symptoms of depression or apathy. However, some aspects of motivation in PD might be affected by non-dopaminergic mechanisms. AIM AND METHOD: The objective of this experimental medicine study was to investigate the contribution of serotonergic modulation via administration of citalopram (20 mg) for 7 days on motivated decision-making in twenty PD patients, measured using several different computerised tasks and clinical questionnaires that probe different aspects of decision-making. Twenty healthy controls were additionally tested without medication to assess any baseline differences between the two groups. RESULTS: Results indicated that PD patients were overall less motivated than controls on an effort- and reward-based decision-making task. Citalopram increased or decreased willingness to exert effort for reward, depending on whether baseline motivation was high or low, respectively. A task assessing decision-making under risk revealed higher levels of risk aversion for potential losses in PD patients, which neither serotonin nor the patient's regular dopaminergic medication seemed to restore. However, citalopram in PD was associated with more risk-seeking choices for gains, although patients and controls did not differ on this at baseline. CONCLUSION: The results provide evidence for a role of the serotonergic system in influencing some aspects of motivated decision-making in PD processes.

Vividness of visual imagery questionnaire scores and their relationship to visual short-term memory performance.

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.

Assessment of apathy in neurological patients using the Apathy Motivation Index caregiver version.

Apathy is a common, disabling neuropsychiatric syndrome that occurs across many brain disorders and may be associated with diminished motivation in behavioural, cognitive, emotional and social domains. Assessment is complicated by the variability of symptoms across apathy domains and self-report from patients, which can be misleading due to their lack of insight. Independent evaluation by clinicians also has limitations though if it has to be performed with limited time. Caregiver reports are a viable alternative, but current assessments for them either do not distinguish between different apathy domains or are interview-based and take long to administer. In this study, we developed a brief caregiver questionnaire version of the recently developed Apathy Motivation Index (AMI), which is a self-report tool. We confirmed three apathy factors in this new caregiver measure (AMI-CG) that were also present in the AMI: Behavioural Activation, Emotional Sensitivity and Social Motivation. Furthermore, we validated the scores against more extensive caregiver interviews using the established Lillle apathy rating scale as well as patient self-reports of apathy, measures of depression, anhedonia, cognition, activities of daily living and caregiver burden across four different neurological conditions: Parkinson's disease, Alzheimer's disease, subjective cognitive impairment and limbic encephalitis. The AMI-CG showed good internal reliability, external validity and diagnostic accuracy. It also uncovered cases of social apathy overlooked by traditional instruments. Crucially, patients who under-rated their apathy compared to informants were more likely to have difficulties performing everyday activities and to be a greater burden to caregivers. The findings provide evidence for a multidimensional conceptualization of apathy and an instrument for efficient detection of apathy based on caregiver reports for use in clinical practice.

Different patterns of short-term memory deficit in Alzheimer's disease, Parkinson's disease and subjective cognitive impairment.

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.

Dopamine Modulates Dynamic Decision-Making during Foraging.

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by traveling elsewhere (background reward rate), to determine the opportunity cost of staying versus leaving. We hypothesized that dopamine specifically modulates the influence of background, but not foreground, reward information when making a dynamic comparison of these variables for optimal behavior. On a novel foraging task based on an ecological account of animal behavior (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background reward rates. In line with theoretical accounts, people's decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signaling the opportunity cost of rewards, not value per se. Using this ecologically derived framework, we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared.SIGNIFICANCE STATEMENT Many decisions, across economic, political, and social spheres, involve choices to "leave". Such decisions depend on a continuous comparison of a current location's value, with that of other locations you could move on to. However, how the brain makes such decisions is poorly understood. Here, we developed a computerized task, based around theories of how animals make decisions to move on when foraging for food. Healthy human participants had to decide when to leave collecting financial rewards in a location, and travel to collect rewards elsewhere. Using a pharmacological manipulation, we show that the activity of dopamine in the brain modulates decisions to move on, with people valuing other locations differently depending on their dopaminergic state.

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.

Baseline impulsivity may moderate L-DOPA effects on value-based decision-making.

Research has indicated a major role of dopamine in decision-making processes, but the underlying mechanisms remain largely unknown due to inconsistency in effects of dopaminergic drugs. To clarify the impact of dopamine on impulsive choice, we administered 150 mg L-DOPA to 87 healthy adults in a randomized, placebo-controlled, double-blind, crossover study, evaluating performance in four value-based decision-making tasks. We predicted that baseline impulsivity would moderate L-DOPA effects. In support of our hypothesis, L-DOPA had no main effect on impulsive choice, but reduced risk-seeking for gains in more-impulsive subjects. Because L-DOPA effects may be influenced by body weight, we repeated our analyses on data from half of the sample (n = 44) with lower weight, anticipating a stronger effect. In addition to the effect on risk-seeking for gains, low-weight participants also exhibited baseline-dependent effects of L-DOPA on loss aversion and delay discounting. Our results are consistent with the hypothesis of an inverted U-shaped dopamine function in which both low and high extremes of dopamine signaling are associated with high-impulsive choice. Consideration of differential baseline impulsivity and body weight may resolve previous seemingly paradoxical pharmacological results and might deepen our understanding of dopaminergic mechanisms underlying impulsivity.

Differential impact of behavioral, social, and emotional apathy on Parkinson's disease.

Apathy is highly prevalent in Parkinson's disease. New findings suggest the syndrome is multifaceted. Here, we investigate whether all aspects of apathy are equally affected in Parkinson's disease and whether different dimensions of apathy were associated with depression and anhedonia. On the Apathy Motivation Index, while behavioral apathy and social apathy were elevated, emotional motivation was relatively preserved in Parkinson's disease, although a few patients did show impaired emotional sensitivity. Behavioral and social, but not emotional, apathy was associated with depression and anhedonia. These findings suggest aspects of motivation can be selectively impaired in Parkinson's disease and may have implications for guiding treatment.

Dopamine Modulates Option Generation for Behavior.

Animals make innumerable decisions every day, each of which involves evaluating potential options for action. But how are options generated? Although much is now known about decision making when a fixed set of potential options is provided, surprisingly little progress has been made on self-generated options. Some researchers have proposed that such abilities might be modulated by dopamine. Here, we used a new measure of option generation that is quantitative, objective, and culture fair to investigate how humans generate different behavioral options. Participants were asked to draw as many different paths (options) as they could between two points within a fixed time. Healthy individuals (n = 96) exhibited a trade-off between uniqueness (how individually different their options were) and fluency (number of options), generating either many similar or few unique options. To assess influence of dopamine, we first examined patients with Parkinson's disease (n = 35) ON and OFF their dopaminergic medication and compared them to elderly healthy controls (n = 34). Then we conducted a double-blind, placebo-controlled crossover study of the D2 agonist cabergoline in healthy older people (n = 29). Across both studies, dopamine increased fluency but diminished overall uniqueness of options generated, due to the effect of fluency trading off with uniqueness. Crucially, however, when this trade-off was corrected for, dopamine was found to increase uniqueness for any given fluency. Three carefully designed control studies showed that performance on our option-generation task was not related to executing movements, planning actions, or selecting between generated options. These findings show that dopamine plays an important role in modulating option generation.