Human working memory and cognitive control

Introduction

Brain dopamine (DA) is well known to play an important role in cognitive control processes, including working memory. This refers to the processes of stabilization and flexibility. The PFC contains a large number of DA receptors and is highly sensitive to its dopaminergic environment. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. In this review the focus is on the role of DA in frontostriatal processing, including working memory and cognitive control, not least because there is a clear anterior/posterior gradient in the brain for the concentration of DA, which is highest in the PFC. The anatomical distribution of the dopaminergic system suggests that it should have a greater influence on anterior than on posterior brain structures.

The effects of dopaminergic drugs often seem paradoxical, because both improvements as well as impairments are observed.

Research is urgent since deficits in working memory and cognitive control are core to disorders like parkinson, schizophrenia, drug addiction and ADHD, which are associated with cognitive inflexibility, impulsivity, and/or compulsivity and secondly because these drugs are used widely.

Review

We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.

Individual differences

A series of studies have replicated the observation that administration of dopaminergic drugs to humans can have diametrically opposite effects on cognition, depending on working memory capacity. It seems that effects of dopaminergic drugs on cognitive function can, at least partly, be predicted from the initial state of the individual.

The relationship between cognitive performance and dopamine (DA) levels follows an “Inverted-U–shaped” function, where both too little and too much DA impairs performance.

Variability in Basal DA Levels in the PFC of Nonhuman Animals

Baseline-dependent effects of DA were first observed by Arnsten and Goldman-Rakic in monkeys performing working memory tasks. Administration of a D1 receptor antagonist impaired performance of young monkeys, but not aged mon- keys with presumed DA depletion. In contrast, a D1 receptor agonist improved performance in aged monkeys, but not in young monkeys.

Also stress-induced working memory deficits were ameliorated by pretreatment with DA receptor antagonists. This finding suggests that excessive DA release in the PFC during stress led to the observed working memory deficits.

Baseline-Dependent Mechanisms of DA Action in Humans

Is there evidence for similar baseline dependency of dopaminergic drug effects in humans? One of the best-studied polymorphisms is the Val158 Met poly- morphism in the catechol-O-methyltransferase (COMT) gene.

Individuals with the Val-allele have relatively high COMT activity and presumably low baseline DA; conversely, individuals with the Met-allele have relatively low COMT activity and presum- ably high baseline DA. Consistent with these assumptions are find- ings that individuals with the Met-allele (high DA) perform signifi- cantly better on tasks requiring cognitive control and working memory than those with the Val variant.

On the other hand, there is no overall effect of the COMT polymorphism on cognition. Rather effects depend on the particular task demands under study and associated neural system, with computations associated specifically with the PFC. The high-DA Met individuals often show lower levels of PFC activity, suggestive of more efficient processing, than the low-DA Val individuals.

These observations from human studies are remarkably consis- tent with those reported in experimental animals.

Distinct Roles for Striatal and PFC DA

Traditionally, cognitive effects of DA are ascribed to modulation of the PFC. However, recent theories as well as empiric data have highlighted a complementary role for DA in the striatum in working memory and cognitive control.

Striatal DA might rather be more important for the ability to flexibly update those goal representations when new information becomes available.

Although we should be flexible in response to task-relevant changes, we should be simultaneously stable as long as the changes are irrelevant. To resolve this apparent paradox, it is more plausible to postulate two separate mechanisms that nevertheless work together.

A study revealed that DA lesions in the PFC led to enhanced distractibility (poor attentional set maintenance), although DA lesions in the striatum actually reduced distractibility (enhanced attentional set maintenance).

This study revealed that optimal DA levels in the PFC might be good for stability but bad for flexibility, whereas optimal DA levels in the striatum might be good for flexibility but bad for stability. Note that, according to this model, supra-optimal levels of DA in the PFC would potentiate stabilization to its extreme, thus inducing perseveration, whereas supra-optimal levels of DA in the striatum would potentiate flexible updating to its extreme, thus inducing distractibility.

PD Studies Strengthen the Link Between DA and Cognition

A different approach toward assessing the influence of DA on cognitive function in humans is by testing patients with PD. Parkin- son’s disease is a progressive, neurodegenerative movement disorder and characterized by a spatiotemporal progression of nigrostriatal and mesocortical DA depletion. In addition to deficits in motor control, PD is also accompanied by significant cognitive impair-ments even in the early stages of the disease. Central nervous system levels of DA can be manipulated over short periods by withdrawing the normal regimen of DA replacement drugs (i.e., levodopa), because the half-life of these drugs is relatively short. Effects can be easily monitored by observing deterioration in the motor status of the patient.

These data confirm that the DA-depleted state of PD is accompanied by changes in cognitive control. However, PD seems to confer either deficits or benefits, depending on the precise task demands under study.

It is hypothesized on the basis of their anatomical pattern of DA depletion, the fMRI data reviewed and the resemblance of the performance pattern to that seen in monkeys with striatal DA lesions that the combination of poor flexibility and good stability in PD patients not taking medication reflects depletion of striatal DA and upregulation of DA in the PFC, respectively. An intriguing pos- sibility is that the restoration of switch- and distractor-costs by dopaminergic medication reflects a normalization of the balance between frontal and striatal DA.

Conclusion

In summary, DA plays a critical role in cognitive control, which is a multifactorial phenomenon that requires a dynamic balance between flexible updating and cognitive stabilization. Understanding the precise effects of DA on these subcomponent processes is not straightforward, partly because the relationship between DA and performance is nonlinear and inverted-U–shaped, with both excessive as well as insufficient levels impairing performance.

In addition, effects of DA depend on the brain region that is targeted, with modulation of one and the same brain region having paradoxical consequences for different subcomponent processes. Specifically, we have put forward a working hypothesis that DA might act at the striatum and the PFC to facilitate flexible updating and cognitive stabilization, respectively. Although this hypothesis likely reflects an oversimplified view of the complex effects of DA on working memory and cognitive control (with different forms of flexible up- dating implicating distinct neural and neurochemical systems), we believe that it provides a plausible starting point for further empirical work.