Role of prefrontal cortex and the midbrain dopamine system in working memory updating

Kimberlee D'Ardenne, Neir Eshel, Joseph Luka, Agatha Lenartowicz, Leigh E. Nystrom, Jonathan D. Cohen

Research output: Contribution to journalArticlepeer-review

192 Scopus citations


Humans are adept at switching between goal-directed behaviors quickly and effectively. The prefrontal cortex (PFC) is thought to play a critical role by encoding, updating, and maintaining internal representations of task context in working memory. It has also been hypothesized that the encoding of context representations in PFC is regulated by phasic dopamine gating signals. Here we use multimodal methods to test these hypotheses. First we used functional MRI (fMRI) to identify regions of PFC associated with the representation of context in a working memory task. Next we used single-pulse transcranial magnetic stimulation (TMS), guided spatially by our fMRI findings and temporally by previous event-related EEG recordings, to disrupt context encoding while participants performed the same working memory task. We found that TMS pulses to the right dorsolateral PFC (DLPFC) immediately after context presentation, and well in advance of the response, adversely impacted context-dependent relative to context-independent responses. This finding causally implicates right DLPFC function in context encoding. Finally, using the same paradigm, we conducted high-resolution fMRI measurements in brainstem dopaminergic nuclei (ventral tegmental area and substantia nigra) and found phasic responses after presentation of context stimuli relative to other stimuli, consistent with the timing of a gating signal that regulates the encoding of representations in PFC. Furthermore, these responses were positively correlated with behavior, as well as with responses in the same region of right DLPFC targeted in the TMS experiment, lending support to the hypothesis that dopamine phasic signals regulate encoding, and thereby the updating, of context representations in PFC.

Original languageEnglish (US)
Pages (from-to)19900-19909
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - Dec 4 2012

All Science Journal Classification (ASJC) codes

  • General


  • Cognitive control
  • Cognitive neuroscience
  • Context updating
  • Task switching


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