Rule-dependent Activity for Prosaccades and Antisaccades in the Primate Prefrontal Cortex Stefan Everling and Joseph F. X. DeSouza Abstract & Everyday life typically requires behavior that involves far more than simple stimulus–response associations. Environ- mental cues are often ambiguous and require different actions depending on the situation. The prefrontal cortex (PFC) is thought to be crucial for this flexible control of behavior. An important task that probes this ability is the antisaccade task in which subjects have to suppress a glance towards a suddenly presented peripheral stimulus and instead look away from the stimulus to its mirror location. Here we recorded the activity of PFC neurons in monkeys trained to alternate between blocks of prosaccade and antisaccade trials with no external instruc- tion cues. We found that the activity of many neurons was different between the two tasks during the fixation period before the peripheral stimulus was presented. These differ- ences were already present on the first correct trials after a task switch. The activity of these neurons also discriminated between correct responses and errors. We hypothesize that the PFC provides bias signals to saccade-related areas that are necessary to preset the oculomotor system for different tasks. & INTRODUCTION The ability to alter behavioral responses to identical stimuli in the face of changing contingencies is especially well developed in primates. A classic neuropsychological task that probes this ability is the Wisconsin Card Sorting Task in which subjects are asked to sort cards according to the color, shape, or number of symbols appearing on them (Milner, 1963). Subjects are provided with feed- back after each match which enables them to acquire the correct classification scheme. After a fixed number of matches, the rule changes without notice and the subject must shift to a new rule of classification. Human patients with lesions of the prefrontal cortex (PFC) can acquire the initial rule but are unable to shift to a new classification rule. Functional neuroimaging studies have confirmed a role of the PFC in set-shifting in humans (Monchi, Petrides, Petre, Worsley, & Dagher, 2001) and nonhuman primates (Nakahara, Hayashi, Konishi, & Miyashita, 2002). Further, nonhuman primates with PFC lesions are impaired in analogous tasks (Dias, Robbins, & Roberts, 1996). Recent single-neuron recording studies in monkeys have begun to reveal neural correlates for rules in the PFC (Wallis, Anderson, & Miller, 2001; Asaad, Rainer, & Miller, 2000; White & Wise, 1999) and in the posterior parietal cortex (Stoet & Snyder, 2004). Neural responses to pictures and during delay periods were found to be different in the PFC between a delayed match-to-sample and a delayed nonmatch-to-sample task (Wallis et al., 2001). The stimuli and the delay periods were identical between the two tasks with the only difference being the behavioral rules that required the monkeys in the first task to decide whether two successively presented pictures were the same and in the second task whether they were different. Indeed, many PFC neurons show differences already in their baseline activity between different tasks. Asaad et al. (2000) recorded single- neuron activity in the PFC while monkeys performed a spatial, an object, and an association task. Neural activity was different for many cells between the three tasks while monkeys were looking at a central fixation point (FP) before a stimulus was presented. The authors suggest that these differences may reflect task-specific activation that might allow conflicting sensory informa- tion to be mapped to the appropriate motor output. All studies so far have investigated the role of the PFC in maintaining or alternating between two or more arbitrary stimulus–response (SR) associations. In every- day life, however, some SR associations are strong and might be executed in a more ‘‘automatic’’ manner, whereas others are weak and require a more ‘‘con- trolled’’ execution (Baddeley, 1986). Strong SR associa- tions are usually those in which the stimulus and the response are compatible, whereas incompatible SR asso- ciations are usually weak. It is, for example, well known from manual SR compatibility tasks that involve spatial stimuli and spatial responses that reaction times are faster and responses are more accurate when the stim- ulus and the response are compatible rather than in- University of Western Ontario, London, Canada D 2005 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 17:9, pp. 1483–1496