ARTICLES https://doi.org/10.1038/s41593-017-0003-2 1 NUS Graduate School of Integrative Science and Engineering, National University of Singapore (NUS), Singapore, Singapore. 2 Department of Electrical and Computer Engineering, NUS, Singapore, Singapore. 3 Department of Psychology, NUS, Singapore, Singapore. 4 Singapore Institute for Neurotechnology, NUS, Singapore, Singapore. 5 Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore. Present address: 6 Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore. Camilo Libedinsky and Shih-Cheng Yen contributed equally to this work. *e-mail: camilo@nus.edu.sg; shihcheng@nus.edu.sg T he prefrontal cortex plays an important role in the mainte- nance of working memory, as evidenced by studies using microelectrode recordings 1 , lesions 2 , inactivation 3 , micro- stimulation 4,5 , and functional neuroimaging 6 . Furthermore, the pre- frontal cortex suppresses task-irrelevant stimuli, or distractors 3,7,8 . This has led to the notion that the prefrontal cortex plays a central role in the maintenance of working memory and the suppression of distractors, which are cornerstones of executive processing. Individual neurons in the lateral prefrontal cortex (LPFC; Brodmann area 46) show selective, sustained activity during the delay period of working memory and only as long as the memory is maintained 1,9,10 . Populations of LPFC neurons form a stable memory code during the delay period of a working memory task 11 . Distractors are thought to be suppressed in the LPFC, since it responds less to distractors than to task-relevant stimuli 3,7,8 . Notably, sustained activ- ity of LPFC neurons persists even after distractors are presented 3,10 . Thus, it is reasonable to hypothesize that the stable code observed during the delay period persists after a distractor is presented, form- ing a persistent code throughout the memory period. Recent studies have shown that the LPFC hosts an abundance of neurons with mixed selectivity 12–19 . These cells encode multiple parameters of the task simultaneously, such as sensory stimuli, task rule, or motor response. In particular, neurons with nonlinear mixed selectivity (NMS) are thought to play a key role in the encoding of information 18,20 . In the context of a working memory task with interfering distractors, mixed selectivity could lead to a change in code after the distractor is presented. Thus, it is also reasonable to hypothesize that the code does not persist throughout the memory period but rather that it is flexible, with the ability to adapt to new task contingencies, such as the presentation of a distractor. Here we found that the LPFC morphs its code, as the latter hypothesis pre- dicts, while the frontal eye fields (FEF) maintain a stable code, in agreement with the former hypothesis. Results Two monkeys were trained to perform a delayed saccade task (Fig. 1a). Overall performance of both animals was higher than 75% correct (Fig. 1b). We recorded a total of 256 neurons from the LPFC (144 from Monkey A and 112 from Monkey B; the posi- tions of the implanted electrode arrays are shown in red in Fig. 1c) and 137 neurons from the FEF (125 from Monkey A and 12 from Monkey B; electrode arrays are shown in blue in Fig. 1c) while the animals performed the task. Of the neurons recorded, more than 40% displayed selectiv- ity to target location in at least one stage during the trial (Fig. 1d). Examples of the responses of an LPFC and an FEF neuron are shown in Supplementary Fig. 1a,b. To quantify the magnitude of this selec- tivity, we computed the percentage of explained variance (PEV) for spatial selectivity in each neuron. The average PEVs across significant neurons (Methods) are shown in Fig. 1d. In the LPFC, we observed that target information in selective cells (n = 107, 42% of the LPFC population) increased during the target presentation period and remained stable throughout the rest of the trial (Fig. 1d). In addition, in Supplementary Fig. 1c, we show that the distractor information was much lower in these same neurons during the Delay 2 period (P < 0.001, Hedges’ g = 23.99). A previous study found a sharp decrease in target information following distractor presen- tation, together with an increase of distractor information 21 . Our results, however, did not replicate these observations. Rather, we found that target information remained stable, and distractor infor- mation stayed close to baseline throughout the trial (Supplementary Fig. 1c). This difference may reflect the simpler nature of our task and the comparatively lower behavioral saliency of the distractor we used. It may also reflect differences in the ways different types of information are encoded; perhaps the working memory code for numerosity in LPFC is more susceptible to distractors than the code for spatial locations. In contrast, in the FEF we observed Mixed selectivity morphs population codes in prefrontal cortex Aishwarya Parthasarathy  1,6 , Roger Herikstad 2 , Jit Hon Bong 2 , Felipe Salvador Medina 3 , Camilo Libedinsky  3,4,5 * and Shih-Cheng Yen  1,2 * The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. Here we show that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. We found that neurons with mixed-selective responses were necessary and suffi- cient for the morphing of code and that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. This suggests that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility. NATURE NEUROSCIENCE | VOL 20 | DECEMBER 2017 | 1770–1779 | www.nature.com/natureneuroscience 1770 © 2017 Nature America Inc., part of Springer Nature. All rights reserved.