To address whether the amygdala is critical for encoding reward value in OFC and MFC, we recorded neural activity in these areas as subjects performed a choice task, both before and after bilateral lesions of the amygdala. The subjects had previously learned that visual stimuli were associated with different magnitudes of reward. As expected, neurons in both OFC and MFC signaled the reward quantity associated with each stimulus. In contrast to MFC, OFC contained a larger proportion of neurons encoding reward quantity and did so with faster response latencies. Removing the amygdala eliminated these differences, mainly by decreasing and slowing value coding in OFC. In addition, the proportion of neurons that encoded the quantity of expected reward and received reward also decreased after the lesions. In effect, the amygdala lesions abolished the preoperative differences between the OFC and MFC. Although the amygdala projects to both OFC and MFC, these findings show that it has its greatest influence over reward value coding in OFC. Importantly, amygdala lesions did not abolish value coding in OFC, which shows that OFCs representations of value depends, in part, on other sources. Our data suggest that any effect of dysfunction or degeneration within the amygdala would primarily affect the processing of emotion and reward valuations within OFC. As part of our effort to understand valuation mechanisms in OFC and MFC, we also investigated the activity of these areas during learning. As indicated above, the amygdala is one source of valuation signals to these two parts of the frontal lobe. To determine whether the amygdala is critical for the development of valuation signals within the OFC and MFC during learning, we recorded neural activity within these areas in subjects performing a learning task both before and after bilateral lesions of the amygdala. Within each session, subjects were given the opportunity to learn about three novel visual stimuli and their associated amounts of fluid reward. Through trial and error, subjects learned to choose the stimulus that led to the greater reward. Amygdala lesions caused a small, but significant, slowing in the rate of learning. Furthermore, these lesions reduced OFCs neural encoding of whether the best stimulus had been chosen on a given trial. By contrast, neurons in MFC displayed an increased coding of the position and value of the chosen stimulus. Taken together, these findings indicate that the amygdala contributes to the incorporation of feedback with stimulus valuations during learning. Recently, there has been renewed interest in the role of the anterior cingulate cortex (ACC), a distinct part of the MFC, in the regulation of emotion and arousal. Dysfunction and degeneration in the ACC has been reported in patients suffering from depression, and its activation in depressed patients is correlated with anhedonia. Based on these findings, therapeutic approaches to treatment-resistant depression have targeted the ACC with electrical stimulation. Determining the role of ACC in positive affect and in arousal would advance our understanding of the neural substrates of emotion and potentially provide a window into the pathophysiology of depression. Accordingly, we assessed the effect of lesions of the ACC on autonomic arousal to positive emotional events. We recorded pupil size, a measure of autonomic and emotional arousal, during Pavlovian conditioning for fluid rewards. Subjects with lesions of ACC and controls exhibited increased pupil size in response to a stimulus that predicted a reward (a conditioned stimulus), but not for a stimulus that had no association with reward. Notably, whereas controls showed a sustained increase in autonomic arousal during a period between the offset of the conditioned stimulus and reward delivery, subjects with lesions of the ACC did not. Lesions of the ACC did not affect extinction of conditioned autonomic arousal, autonomic arousal in response to the delivery of rewards alone, or the acquisition and extinction of object-reward associations. Our data reveal that the ACC is important for sustaining autonomic arousal in anticipation of positive emotional events, such as rewards, and suggest a specific role for this area in the regulation of arousal and emotion. Relative to neutral stimuli, arousing visual stimuli produce greater fMRI activation within the inferior temporal cortex (IT) and the amygdala. This affective modulation could underlie emotional attention, a mechanism through which biologically important stimuli capture neural resources devoted to sensory processing. The emotional-attention effect in IT could derive from three sources: (1) direct amygdala projections to IT;(2) a subcortical loop involving the striatum;and/or (3) direct projections from the OFC and the ventral prefrontal cortex to IT. Using visual stimuli, we used fMRI to measure cortical activation in subjects after they had learned stimulus-reward associations in sessions composed of two types of trials. One type of trial involved a forced choice between two visual stimuli. The other type, interleaved with the first, involved Pavlovian viewing-only trials. Half of the stimuli predicted a high probability of reward and half predicted a low probability. To measure reward expectation, we compared activations on viewing-only trials, contrasting the response to stimuli predicting a high probability of reward with those predicting a low probability. After learning, subjects chose the high probability stimulus on about 90 percent of choice trials, which shows that they attended to and learned about the valuations of the visual stimuli. We found significantly greater activation in response to the high probability stimuli in both the amygdala and IT. The effect was specific for emotional attention in IT, as shown by the observation that the activated regions did not respond to receipt of reward per se. These results demonstrate that the amygdala and IT encode reward probability, and that reward-related responses in IT cortex are specific for emotional attention.

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U.S. National Institute of Mental Health
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Rudebeck, Peter H; Putnam, Philip T; Daniels, Teresa E et al. (2014) A role for primate subgenual cingulate cortex in sustaining autonomic arousal. Proc Natl Acad Sci U S A 111:5391-6