UC Berkeley

The integrity of the dopamine system is critical for high-level cognitive functions such as attentional processing. Patients with dopaminergic disorders demonstrate deficits across numerous tasks manipulating the allocation of attentional resources, and individual differences in dopamine activity correlate with task performance in healthy subjects. This dissertation uses positron emission tomography (PET), functional magnetic resonance imaging (fMRI), neuropsychological testing, and functional genetic polymorphisms to investigate how dopamine modulates brain networks to influence cognitive performance and specific attentional processes.

The first finding presents a model of the mechanism, at the systems level, whereby a genetic polymorphism in the dopamine system influences cognition. Catechol-O-methyltransferase (COMT) is an enzyme that degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. The results show that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. These results suggest that COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.

The second finding shows that dopamine influences the shifting of attentional resources between the internal and the external environment by modulating the coupling of brain networks involved in attentional processes. fMRI studies of attention have revealed the importance of three brain networks: a dorsal attention network (DAN), a default mode network (DMN), and a fronto-parietal control network (FPCN). The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The fronto-parietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the fronto-parietal control network and the default mode network while reducing the coupling between the fronto-parietal control network and the dorsal attention network. These results add a neurochemical perpective to the role of network interaction in modulating attention.

The third finding shows that, in addition to supporting the transition between internal and external attention, dopamine also modulates the shifting of attention between perceptual features of objects. Attentional shifting can be conceptualized as at least two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with attentional shifting, but patients with dopaminergic deficits are not impaired on all tasks assessing attentional shifting, suggesting that dopamine may have different roles in the shifting of objects and rules. The results did not associate shifts of abstract rules with activation in any brain region, and dopamine did not correlate with rule shift performance. Shifting between object features deactivated the medial prefrontal cortex and the posterior cingulate and activated the lateral prefrontal cortex, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial prefrontal cortex, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.

The integration of these findings shows that a gene in the dopamine system influences cognition via dopamine synthesis capacity, resting state fMRI activity and task-related fMRI activity, and that the specific role of dopamine in cognition may be the modulation of attentional processes.