Department of Chemistry, Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA.
Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):19900-9. doi: 10.1073/pnas.1116727109. Epub 2012 Oct 18.
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.
人类善于快速有效地在目标导向行为之间切换。前额叶皮层（PFC）被认为通过在工作记忆中对任务上下文的内部表示进行编码、更新和维持来发挥关键作用。人们还假设 PFC 中上下文表示的编码受相位多巴胺门控信号的调节。在这里，我们使用多模态方法来检验这些假设。首先，我们使用功能磁共振成像（fMRI）来识别与工作记忆任务中上下文表示相关的 PFC 区域。接下来，我们使用单脉冲经颅磁刺激（TMS），根据我们的 fMRI 发现进行空间引导，并根据之前的事件相关 EEG 记录进行时间引导，在参与者执行相同的工作记忆任务时干扰上下文编码。我们发现，TMS 脉冲在上下文呈现后立即刺激右侧背外侧前额叶皮层（DLPFC），并且在反应之前，会对上下文相关的反应产生不利影响，而对上下文无关的反应则没有影响。这一发现将右侧 DLPFC 的功能归因于上下文编码。最后，使用相同的范式，我们在脑干多巴胺能核（腹侧被盖区和黑质）中进行了高分辨率 fMRI 测量，并发现相对于其他刺激，在呈现上下文刺激后出现了相位反应，这与调节 PFC 中表示编码的门控信号的时间一致。此外，这些反应与行为以及 TMS 实验中靶向右侧 DLPFC 相同区域的反应呈正相关，这支持了多巴胺相位信号调节编码，从而更新 PFC 中上下文表示的假设。
