Amygdala lesions do not compromise the cortical network for false-belief reasoning

The amygdala plays an integral role in human social cognition and behavior, with clear links to emotion recognition, trust judgments, anthropomorphization, and psychiatric disorders ranging from social phobia to autism. A central feature of human social cognition is a theory-of-mind (ToM) that enables the representation other people''s mental states as distinct from one''s own. Numerous neuroimaging studies of the best studied use of ToM—false-belief reasoning—suggest that it relies on a specific cortical network; moreover, the amygdala is structurally and functionally connected with many components of this cortical network. It remains unknown whether the cortical implementation of any form of ToM depends on amygdala function. Here we investigated this question directly by conducting functional MRI on two patients with rare bilateral amygdala lesions while they performed a neuroimaging protocol standardized for measuring cortical activity associated with false-belief reasoning. We compared patient responses with those of two healthy comparison groups that included 480 adults. Based on both univariate and multivariate comparisons, neither patient showed any evidence of atypical cortical activity or any evidence of atypical behavioral performance; moreover, this pattern of typical cortical and behavioral response was replicated for both patients in a follow-up session. These findings argue that the amygdala is not necessary for the cortical implementation of ToM in adulthood and suggest a reevaluation of the role of the amygdala and its cortical interactions in human social cognition.The amygdala is considered a critical node of the “social brain” that contributes to myriad social behaviors exhibited by primates (1–4). Neurons in both the monkey (5) and human amygdala (6) respond prominently to faces, and lesions of the monkey amygdala result in complex impairments in social behavior (7, 8). Rare bilateral lesions of the amygdala in human patients impair the ability to infer emotions from facial expressions (9, 10), to make more complex social judgments from faces (11), and to guide appropriate social behaviors (12).A core social ability of humans that emerges early in childhood has been long studied under the name of “theory-of-mind” (ToM), an ability to impute mental states to other people. Amygdala lesions can impair the ability to impute such mental states spontaneously to animated geometric shapes (13, 14) as well as other complex expressions of ToM (15). These impairments in social cognition following amygdala lesions also have been compared with the intensively studied impairments in mental-state understanding observed in autism spectrum disorder (16, 17). Indeed, the amygdala has been implicated in emotional and social dysfunction in a number of psychiatric disorders (18).Neuroimaging studies of ToM-related abilities, on the other hand, have focused largely on cortical networks (19, 20). One of these networks, based on using a localizer requiring subjects to infer false beliefs from written stories (the “False-Belief Localizer”) (21, 22) has become so well established that it is commonly referred to as the “ToM network” and prominently includes the temporoparietal junction as well as medial frontoparietal and anterior temporal cortices (23–28).If the amygdala plays a critical role in social cognition, why is it not regularly identified in neuroimaging studies of ToM? One answer may be that these studies have been focused more on cortical networks, and possible amygdala activations are either underreported or underdiscussed. A second answer may be that the blood oxygenation level-dependent (BOLD) response is more difficult to evoke in the amygdala than in cortex (29, 30). However, the amygdala’s vast connectivity with most of the neocortex (31), prominently including some of the key nodes of the false-belief network such as the medial prefrontal cortex (32, 33), together with its role in social cognition reviewed above, justifies a strong hypothesis. That hypothesis is that the cortical false-belief network should include or be modulated by the amygdala. The clear prediction from this hypothesis is that lesions of the amygdala should alter the functional response of cortical regions critical to ToM.To test this prediction in the most direct way, we used functional MRI (fMRI) in two rare patients with bilateral amygdala lesions and closely interrogated BOLD responses within the amygdala in a large group of neurologically healthy controls. The patients with amygdala lesions had developmental-onset calcifications of the amygdala resulting from Urbach–Wiethe disease (34) (raising interesting further questions about the possible developmental contributions of the amygdala to the false-belief reasoning network, issues we take up in Discussion). To evoke false-belief network activation, each patient performed the well-established False-Belief Localizer twice in separate MRI sessions. The False-Belief Localizer (often called simply the “ToM Localizer”) developed by Rebecca Saxe and colleagues (21, 22) uses brief verbal narratives to manipulate the demand to represent another person''s false belief about reality.At the outset, we clarify that the False-Belief Localizer does not exhaustively represent the range and complexity of the human capacity to reason about mental states (35). In fact, many different behavioral tasks have been used to manipulate mental-state reasoning in previous neuroimaging studies (23, 26), and recent evidence has demonstrated convincingly that these various tasks are not interchangeable manipulations of a single ToM capacity but rather modulate dissociable cortical networks (28, 36). Nonetheless, several reasons justify our decision to focus here on the False-Belief Localizer. First, given that false-belief representation historically has been considered the most unequivocal expression of ToM (37), theory and research on ToM has long maintained a central focus on the capacity to represent false beliefs (38, 39). Second, the focus of ToM research on false-belief reasoning has remained strong in neuroimaging studies of social cognition, in large part because of the efforts of Saxe and colleagues (21, 22) to optimize and make publicly available an efficient protocol for this purpose. Because this same basic protocol has been used in numerous neuroimaging studies of neurologically healthy adults, it is now possible to generate large empirical distributions against which new data points can be compared (40). Therefore, the present study tests the hypothesis that cortical function during false-belief reasoning would show abnormalities in the absence of the amygdala, using this same false-belief neuroimaging task.