Inverted-U-shaped dopamine actions on human working memory and cognitive control

Abstract

Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. 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. 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.

Figure 1

The relationship between cognitive performance and DA levels follows an ‘Inverted U-shaped’ function, where both too little and too much DA impairs performance. How likely it is that a drug will cause beneficial or detrimental effects depends partly on basal dopamine levels. A single ∩ curve is insufficient to predict performance: Some tasks benefit from increasing dopamine (green), while performance on other tasks is disrupted by increasing dopamine (red). The black arrow represents the dopamine-enhancing effect of a hypothetical drug, leading to a beneficial effect on task A (red), but a detrimental effect on task B (green). Reproduced with permission from Cools and Robbins [13].

Figure 2

(a) The mean raw axial (MR co-registered) whole-brain FMT PET K_i images from the high-span group (left panel) and from the low-span group (right panel) overlaid on a normalized MR image. Data represent K_i-values. Right is right according to neurological conventions; (b) Correlation between working memory capacity (on the x-axis: listening span) and dopamine synthesis capacity in the striatum (on the y-axis: K_i values from the left caudate nucleus). Adapted with permission from Figure 1 and 2 from Cools et al [89].

Figure 3

The effects of dopamine receptor stimulation depend on task demands and neural site of modulation. (a) A delayed match-to-sample (DMS) task was used that provide a measure of flexible updating (cognitive switching during encoding) as well as a measure of stabilization (distractor-resistence during the delay). Subjects memorized faces or scenes depending on the color of the fixation cross. Subjects occasionally switched between encoding faces and scenes. A distractor was presented during a delay. Subjects were instructed to ignore this distractor. (b) Top panel: Effects of bromocriptine on striatal activity during updating as a function of group (the group × drug interaction effect, whole-brain contrast values (> 25) are overlaid on 4 coronal slices [slice numbers displayed on top] from the Montreal Neurological Institute high-resolution single subject MR image; Abbreviations: L = left; R = right) (note that the effect in the dorsomedial frontal cortex did not reach significance after correction for multiple comparisons); Bottom panel: Effects of bromocriptine on updating-related activity in the striatum and left PFC in low-span subjects only. (c) Top panel: Effects of bromocriptine on frontal activity during stabilization as a function of group (the group × drug interaction effect, all contrast values > 25 shown); Bottom panel: Effects of bromocriptine on distractor-related activity in the striatum and left PFC in low-span subjects only. Reproduced and adapted with permission from Cools et al [45].