Sean James Fallon

Working Memory Capacity Predicts Effects of Methylphenidate on Reversal Learning

Increased use of stimulant medication, such as methylphenidate, by healthy college students has raised questions about its cognitive-enhancing effects. Methylphenidate acts by increasing extracellular catecholamine levels and is generally accepted to remediate cognitive and reward deficits in patients with attention deficit hyperactivity disorder. However, the cognitive-enhancing effects of such ‘smart drugs’ in the healthy population are still unclear. Here, we investigated effects of methylphenidate (Ritalin, 20 mg) on reward and punishment learning in healthy students (N=19) in a within-subject, double-blind, placebo-controlled cross-over design. Results revealed that methylphenidate effects varied both as a function of task demands and as a function of baseline working memory capacity. Specifically, methylphenidate improved reward vs punishment learning in high-working memory subjects, whereas it impaired reward vs punishment learning in low-working memory subjects. These results contribute to our understanding of individual differences in the cognitive-enhancing effects of methylphenidate in the healthy population. Moreover, they highlight the importance of taking into account both inter- and intra-individual differences in dopaminergic drug research.

Causes and consequences of limitations in visual working memory

Recent methodological and conceptual advances have led to a fundamental reappraisal of the nature of visual working memory (WM). A large corpus of evidence now suggests that there might not be a hard limit on the number of items that can be stored. Instead, WM may be better captured by a highly limited––but flexible––resource model. More resource can be allocated to prioritized items but, crucially, at a cost of reduced recall precision for other stored items. Expectations may modulate resource distribution, for example, through neural oscillations in the alpha band increasing inhibition of irrelevant cortical regions. Our understanding of the neural architecture of WM is also undergoing radical revision. Whereas the prefrontal cortex has previously dominated research endeavors, other cortical regions, such as early visual areas, are now considered to make an essential contribution, for example holding one or more items in a privileged state or “focus of attention” within WM. By contrast, the striatum is increasingly viewed as crucial in determining why and how items are gated into memory, while the hippocampus, it has controversially been argued, might be critical in the formation of temporally resilient conjunctions across features of stored items in WM.

The neurocognitive cost of enhancing cognition with methylphenidate: Improved distractor resistance but impaired updating

A balance has to be struck between supporting distractor-resistant representations in working memory and allowing those representations to be updated. Catecholamine, particularly dopamine, transmission has been proposed to modulate the balance between the stability and flexibility of working memory representations. However, it is unclear whether drugs that increase catecholamine transmission, such as methylphenidate, optimize this balance in a task-dependent manner or bias the system toward stability at the expense of flexibility (or vice versa). Here we demonstrate, using pharmacological fMRI, that methylphenidate improves the ability to resist distraction (cognitive stability) but impairs the ability to flexibly update items currently held in working memory (cognitive flexibility). These behavioral effects were accompanied by task-general effects in the striatum and opposite and task-specific effects on neural signal in the pFC. This suggests that methylphenidate exerts its cognitive enhancing and impairing effects through acting on the pFC, an effect likely associated with methylphenidates action on the striatum. These findings highlight that methylphenidate acts as a double-edged sword, improving one cognitive function at the expense of another, while also elucidating the neurocognitive mechanisms underlying these paradoxical effects.

Learning to be inflexible: Enhanced attentional biases in Parkinson's disease.

Impaired attentional flexibility is considered to be one of the core cognitive deficits in Parkinsons 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 alters the fidelity of working memory representations according to attentional demands

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.

Fractionating the Neurocognitive Mechanisms Underlying Working Memory: Independent Effects of Dopamine and Parkinson's Disease.

Abstract Deficits in working memory (WM) in Parkinsons disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter‐resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time.

Ignoring versus updating in working memory reveal differential roles of attention and feature binding

Ignoring distracting information and updating current contents are essential components of working memory (WM). Yet, although both require controlling irrelevant information, it is unclear whether they have the same effects on recall and produce the same level of misbinding errors (incorrectly joining the features of different memoranda). Moreover, the likelihood of misbinding may be affected by the feature similarity between the items already encoded into memory and the information that has to be filtered out (ignored) or updated into memory. Here, we investigate these questions. Participants were sequentially presented with two pairs of arrows. The first pair of arrows always had to be encoded into memory, but the second pair either had to be ignored (ignore condition) or allowed to displace the previously encoded items (update condition). To investigate the effect of similarity on recall, we also varied, in a factorial manner, whether the items that had to be ignored or updated were presented in the same or different colours and/or same or different spatial locations to the original memoranda. By applying a computational model, we were able to quantify the levels of misbinding. Ignoring, but not updating, increased overall recall error as well as misbinding rates, even when accounting for the retention period. This indicates that not all manipulations of attention in WM are equal in terms of their effects on recall and misbinding. Misbinding rates in the ignore condition were affected by the colour and spatial congruence of relevant and irrelevant information to a greater extent than in the update condition. This finding suggests that attentional templates are used to evaluate relevant and irrelevant information in different ways during ignoring and updating. Together, the results suggest that differences between the two functions might occur due to higher levels of attentional compartmentalisation – or protection – during updating compared to ignoring.

Hemispheric Asymmetry of Globus Pallidus Explains Reward-related Posterior Alpha Modulation in Humans

Although basal ganglia (BG) functions have been widely explored in relation to motor control, recent evidence suggests that their mechanisms extend to the domain of attentional switching. We here investigated the BG involvement in reward related top-down control of visual alpha-band oscillations (8-13 Hz), which have been linked to the mechanisms supporting the allocation of spatial attention. Given that items associated with contextual saliency (e.g. monetary reward or loss) attract attention, it is not surprising that alpha oscillations are further modulated by the saliency properties of the visual items. The executive network controlling such reward-dependent modulations of oscillatory brain activity has yet to be elucidated, and likely relies on the contribution of subcortical regions. To uncover this, we investigated whether derived measures of basal ganglia (BG) structural asymmetries could predict interhemispheric modulation of alpha power, during a spatial attention task. We show that volumetric lateralization of the globus pallidus (GP) significantly explains individual hemispheric biases in alpha power modulation. Importantly, this effect varied as a function of value-saliency parings in the task. We hence provide compelling evidence suggesting that the GP in humans is a node within the executive control network, implicated in reward related top-down control of visual alpha oscillations during saliency processing.While subcortical structures like the basal ganglia have been widely explored in relation to motor control, recent evidence suggests that their mechanisms extend to the domain of attentional switching. We here investigated the subcortical involvement in reward related top-down control of visual alpha-band oscillations (8 – 13 Hz), which have been consistently linked to mechanisms supporting the allocation of visuo-spatial attention. Given that items associated with contextual saliency (e.g. monetary reward or loss) attract attention, it is not surprising that the acquired salience of visual items further modulates. The executive networks controlling such reward-dependent modulations of oscillatory brain activity have yet to be fully elucidated. Although such networks have been explored in terms of cortico-cortical interactions, subcortical regions are likely to be involved. To uncover this, we combined MRI and MEG data from 17 male and 11 female participants, investigating whether derived measures of subcortical structural asymmetries predict interhemispheric modulation of alpha power during a spatial attention task. We show that volumetric hemispheric lateralization of globus pallidus (GP) and thalamus (Th) explains individual hemispheric biases in the ability to modulate posterior alpha power. Importantly, for the GP, this effect became stronger when the value-saliency parings in the task increased. Our findings suggest that the GP and Th in humans are part of a subcortical executive control network, differentially involved in modulating posterior alpha activity in the presence of saliency. Further investigation aimed at uncovering the interaction between subcortical and neocortical attentional networks would provide useful insight in future studies. Significance statement While the involvement of subcortical regions into higher level cognitive processing, such as attention and reward attribution, has been already indicated in previous studies, little is known about its relationship with the functional oscillatory underpinnings of said processes. In particular, interhemispheric modulation of alpha band (8-13Hz) oscillations, as recorded with magnetoencephalography (MEG), has been previously shown to vary as a function of salience (i.e. monetary reward/loss) in a spatial attention task. We here provide novel insights into the link between subcortical and cortical control of visual attention. Using the same reward-related spatial attention paradigm, we show that the volumetric lateralization of subcortical structures (specifically Globus Pallidus and Thalamus) explains individual biases in the modulation of visual alpha activity.

Motivation dynamically increases noise resistance by internal feedback during movement.

&NA; Motivation improves performance, pushing us beyond our normal limits. One general explanation for this is that the effects of neural noise can be reduced, at a cost. If this were possible, reward would promote investment in resisting noise. But how could the effects of noise be attenuated, and why should this be costly? Negative feedback may be employed to compensate for disturbances in a neural representation. Such feedback would increase the robustness of neural representations to internal signal fluctuations, producing a stable attractor. We propose that encoding this negative feedback in neural signals would incur additional costs proportional to the strength of the feedback signal. We use eye movements to test the hypothesis that motivation by reward improves precision by increasing the strength of internal negative feedback. We find that reward simultaneously increases the amplitude, velocity and endpoint precision of saccades, indicating true improvement in oculomotor performance. Analysis of trajectories demonstrates that variation in the eye position during the course of saccades is predictive of the variation of endpoints, but this relation is reduced by reward. This indicates that motivation permits more aggressive correction of errors during the saccade, so that they no longer affect the endpoint. We suggest that such increases in internal negative feedback allow attractor stability, albeit at a cost, and therefore may explain how motivation improves cognitive as well as motor precision.

Occipital Alpha and Gamma Oscillations Support Complementary Mechanisms for Processing Stimulus Value Associations

Selective attention is reflected neurally in changes in the power of posterior neural oscillations in the alpha (8–12 Hz) and gamma (40–100 Hz) bands. Although a neural mechanism that allows relevant information to be selectively processed has its advantages, it may lead to lucrative or dangerous information going unnoticed. Neural systems are also in place for processing rewarding and punishing information. Here, we examine the interaction between selective attention (left vs. right) and stimuluss learned value associations (neutral, punished, or rewarded) and how they compete for control of posterior neural oscillations. We found that both attention and stimulus–value associations influenced neural oscillations. Whereas selective attention had comparable effects on alpha and gamma oscillations, value associations had dissociable effects on these neural markers of attention. Salient targets (associated with positive and negative outcomes) hijacked changes in alpha power—increasing hemispheric alpha lateralization when salient targets were attended, decreasing it when they were being ignored. In contrast, hemispheric gamma-band lateralization was specifically abolished by negative distractors. Source analysis indicated occipital generators of both attentional and value effects. Thus, posterior cortical oscillations support both the ability to selectively attend while at the same time retaining the ability to remain sensitive to valuable features in the environment. Moreover, the versatility of our attentional system to respond separately to salient from merely positively valued stimuli appears to be carried out by separate neural processes reflected in different frequency bands.