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. 2013 Jul 15;74(2):99-105.
doi: 10.1016/j.biopsych.2012.10.032. Epub 2012 Dec 27.

A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility

Gregory R Samanez-Larkin  1 , Joshua W Buckholtz, Ronald L Cowan, Neil D Woodward, Rui Li, M Sib Ansari, Catherine M Arrington, Ronald M Baldwin, Clarence E Smith, Michael T Treadway, Robert M Kessler, David H Zald
Affiliations

A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility

Gregory R Samanez-Larkin et al. Biol Psychiatry. .

Abstract

Background: Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching.

Methods: Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [(18)F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release.

Results: The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release.

Conclusions: These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement.

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Conflict of interest statement

Financial Disclosures

All authors report no biomedical financial interest or potential conflicts of interest.

Figures

Figure 1
Figure 1
The behavioral measure of inflexibility (switch cost = SC) was reduced with an oral dose of amphetamine for most participants. ms = milliseconds. Grey line is unity line (placebo switch cost = d-AMPH switch cost). N = 40
Figure 2
Figure 2
Increases in cognitive flexibility (reductions in switch cost) were associated with dopamine D2/D3 binding potential in the lateral frontal cortex (a), thalamus (b), and parietal cortex (c). Scatterplot y-axis is size of switch cost reduction from placebo to d-AMPH in milliseconds (d-AMPH SC Δ). Scatterplot is displayed only as a sample depiction of effects to illustrate the absence of outliers. N = 40
Figure 3
Figure 3
Increases in cognitive flexibility (reductions in switch cost) were associated with dopamine release in the caudate. Scatterplot y-axis is size of switch cost reduction from placebo to d-AMPH in milliseconds (d-AMPH SC Δ). Scatterplot is displayed only as a sample depiction of effects to illustrate the absence of outliers. N = 40
Figure 4
Figure 4
Structural equation model of the thalamocorticostriatal network effects on psychostimulant-enhanced cognitive flexibility. Path coefficients are standardized regression betas. The path between the thalamic-cortical latent variable and the thalamus manifest variable was fixed to an unstandardized coefficient of 1 during estimation. All paths are significant at p < .05. Encircled e’s are residual error variance terms. d-AMPH SC Δ = switch cost reduction from placebo to d-AMPH (expressed as an increase in flexibility)
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