Cerebral Cortex Advance Access originally published online on January 11, 2007
Cerebral Cortex 2007 17(11):2593-2600; doi:10.1093/cercor/bhl166
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Unilateral Amygdala Lesions Hamper Attentional Orienting Triggered by Gaze Direction
1 Department of Psychiatry, Komagino Hospital, Tokyo, Japan, 2 Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan, 3 Department of Psychology, Keio University, Tokyo, Japan
Address correspondence to Tomoko Akiyama, MD, Komagino Hospital, 273 Uratakao-cho Hachioji City, Tokyo 193-8505, Japan. Email: tee-i{at}mxv.mesh.ne.jp.
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Abstract |
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The newly discovered deficit in a bilateral amygdala-damaged case, of not being able to allocate attention to the critical feature of a face (Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR. 2005. A mechanism for impaired fear recognition after amygdala damage. Nature. 433:68--72.), has opened a new window into the function of the amygdala. This case implies that the amygdala might be essential in detecting potentially relevant social stimuli, and directing attention accordingly. In this study, we have sought to test this implication by investigating the behavioral performance of 5 unilateral amygdala-damaged subjects on spatial cueing tasks. The tasks employed central gaze and arrow direction as cues to trigger attentional orienting in peripheral target detection. Although age-matched normal controls demonstrated a significant congruency effect such that targets presented congruently to cue direction elicited faster detection, amygdala subjects demonstrated no such congruency effect for gaze cues in the face of a significant congruency effect for arrow cues. The results suggest that the social valence of a stimulus is critical for amygdala involvement in visual processing. The results also support the implicated role of the amygdala in detecting and analyzing relevant social stimuli, and orienting attention accordingly.
Key Words: amygdala laterality • arrow • social cognition • spatial cueing
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Introduction |
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The amygdala has captured much interest for its intriguing function in processing the emotional valence of a stimulus, and modulating perception, behavior, and memory based on such valence. In the growing field of social cognition, a rather specific role of the amygdala in recognizing fearful faces has been repeatedly demonstrated in both neuropsychological (Adolphs et al. 1994
, 1999) and neurofunctional (Morris et al. 1996; Whalen et al. 1998) studies. More specifically, the importance of the eye region in fearful faces has been emphasized through functional neuroimaging studies where fearful eyes (Morris et al. 2002), and even fearful eye-whites (Whalen et al. 2004) have been shown to be sufficient in activating the amygdala. Recently, a further role of the amygdala has been identified in a bilateral amygdala-damaged case, SM, who failed to make gaze fixations on the critical feature of faces, that is, the eyes, thereby hampering her ability to decipher emotion expressed through faces (Adolphs et al. 2005). The finding from this case thus indicates that the amygdala does not merely process incoming emotional stimulus but actually participates in seeking for relevant stimulus from the environment, and allocating attention toward it. Indeed, a number of functional neuroimaging studies have demonstrated that aversive faces that escape conscious awareness, as when unattended to due to competing stimuli (Vuilleumier et al. 2001; Anderson et al. 2003; Williams et al. 2004), when subliminally presented (Morris et al. 1998; Whalen et al. 1998; Nomura et al. 2004), or even when unperceived due to blindsight (Morris et al. 2001), are nonetheless captured by the amygdala as seen in its activation. However, to date, few neuropsychological investigations have addressed the impact of amygdala lesion on attention; Anderson and Phelps (2001) have reported that left (and bilateral) amygdala lesions diminish the attentional enhancement normally seen to aversive over neutral words. Vuilleumier et al. (2004) have demonstrated that the enhancement of fusiform activation, which is normally present to fearful over neutral faces, was absent in left and right amygdala-damaged subjects, irrespective of attentional factors (i.e., whether the stimuli faces were attended to or not). The effect of amygdala lesion on attentional orienting behavior, such as implicated through the case of SM (Adolphs et al. 2005), is an intriguing issue that has not yet been fully addressed.
A potential experimental paradigm to test the implicated role of the amygdala in orienting attention toward relevant stimuli is the spatial cueing task using cues such as gaze and arrow direction (Friesen and Kingstone 1998; Tipples 2002). In these tasks, where central gaze/arrow is used to trigger attentional orienting, normal subjects have repeatedly demonstrated faster reaction times (RTs) in detecting peripheral targets presented congruently to the cue direction, opposed to incongruently presented targets. Given the numerous data of amygdala involvement in gaze processing (Brothers and Ring 1993; Young et al. 1995; Broks et al. 1998; Kawashima et al. 1999; George et al. 2001; Morris et al. 2002; Adams et al. 2003; Hooker et al. 2003; Whalen et al. 2004; Adolphs et al. 2005), the employment of gaze direction in such tasks would have an additional value of directly examining the impact of amygdala lesion on gaze processing. On the other hand, arrow cues would give us the opportunity to investigate whether any compromise that might be present in amygdala-damaged subjects is selective to gaze, or generalizes to other relevant signals. When considering the nature of the amygdala function in optimizing adaptation and survival, social cues such as fearful faces and gaze direction might not necessarily be the only relevant stimuli to "capture the amygdala's attention"; nonhuman animates (snakes), objects (guns), natural phenomenon (lightening), words ("caution"), and symbols (skull and crossbones) might all equally capture attention for better adaptation and survival. Likewise, an arrow sign is an overlearned symbol that can effectively modulate orienting behavior in healthy subjects (Tipples 2002), a phenomenon most likely attributable to the conveyed intention behind the arrow sign: "Look over there!"
The outstanding question that we have set out to address in this report is whether amygdala lesion affects attentional orienting triggered by relevant cues, and if so, whether there is any distinction between social and nonsocial cues. Here, we have tested 5 subjects with unilateral amygdala lesions in spatial cueing tasks employing gaze and arrow cues. If indeed, social stimuli such as eyes enjoy preferential processing in the amygdala, the amygdala-damaged subjects might demonstrate impaired gaze-triggered, but intact arrow-triggered orienting. Conversely, if the amygdala processes relevant stimuli irrespective of social valence, orienting triggered by both cues might be uniformly hampered.
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Subjects
Five subjects with unilateral amygdala lesion (right, 2; left, 3) participated in the study. The demographic data, such as the etiology, present medication, and present intelligent quotient (IQ) are shown in Table 1. Note that general attention, as indicated by the attention/concentration index of Wechsler memory scale-revised (WMS-R) (also shown in Table 1), is in the superior range for each subject. Case 1 demonstrates antisocial behavior, such as getting into numerous street fights, and lives on welfare. Case 2 became mildly depressive after recovery but is able to work full-time as a nurse. Case 3 presented with ictal fear at onset, which diminished within a month. He returned to his office work after recovery. Case 4 became emotionally withdrawn after surgery with some depressive symptoms, and is taking a long leave from work. Case 5 also became increasingly withdrawn after surgery, and is easily provoked. He has returned to his office job but remains socially withdrawn both at work and home. Magnetic resonance imaging (MRI) slices depicting the amygdala lesion are presented for each subject in Figure 1. Fifteen normal volunteers also participated as controls. The exclusion criteria were a psychiatric history and a neurological history. All participants had normal or corrected-to-normal vision.
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Prior to the experiment, all 5 amygdala subjects were evaluated on conventional tests assessing spatial attention and visuomotor processing, as these functions are essential in performing the following experimental task. For spatial attention, Cancellation Test (for the numeral "3" and the Japanese character "ka"), and Tapping Span Test were administered, both of which were in the normal range based on the previously accumulated normative data (Table 2). Symbol Digit Modalities Test (SDMT) was used to assess visuomotor processing, tracking, and motor speed. In this test, a series of 9 geometric symbols, each of which were labeled with a number from 1 to 9, were presented. The subjects were required to substitute the symbols with the corresponding numbers as fast as possible within the given 90 s. The percentage of correct responses achieved (maximum 110) was evaluated. Again, the amygdala group performed within the normal range (Table 2). The performance of the amygdala subjects on the following experimental task can thus be concluded to be unconfounded by deficits in spatial attention or visuomotor processing capacities per se.
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This study was approved by the ethical committee at our institutions, and all subjects gave their informed consent to participation.
Stimuli
The experiment was controlled by Superlab software, and the stimuli were presented on a 14-inch computer monitor. There were 3 blocks to the experiment, each with a different stimulus for the cue. The cues were black line drawings representing: Arrows for the first block, Eyes for the second, and Faces for the third block, as illustrated in Figure 2.
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In the first, Arrow block, a cross subtending 3.9° horizontally and 1.9° vertically appeared in the center, of which the intersection served as the fixation point. This was displayed for 675 ms, followed by the cue display. In the cue display, arrowheads or vertical bars appeared at each horizontal end of the cross. Arrowheads (1.3° x 0.6°) at both ends pointed in the same direction, cueing either to the right or left. The vertical bars (1.3°) served as the neutral cue, similar to straight gaze in the second block. The cue was presented for either 100, 300, or 700 ms randomly (stimulus onset asynchrony; SOA), after which a target, X, subtending 0.6°, appeared either to the right or left of the cue, 7.1° from the fixation point. Note that the cue remained displayed throughout target presentation.
In the second, Eyes block, the fixation display was composed of one central circle subtending 0.4°, and 2 ellipses, the axes of which are 1.8° x 0.9°, and the center of which is 1.0° above, and 1.4° to the left and right of the central circle. The central circle was used as the fixation point, and was displayed for 675 ms, followed by the cue display. In the cue display, a black circle subtending 0.9°, appeared within each ellipse, positioned either centrally (straight gaze), or 11% off the center to the right or left (right/ left gaze). The cue was presented for either 100, 300, or 700 ms randomly, after which a target, X, subtending 0.6°, appeared either to the right or left of the cue, 7.1° from the central circle. Again, the cue remained displayed throughout target presentation. The third, Face block was identical to the Eyes block, except for the additional large circle subtending 8.0°, which surrounded the eyes and served as the facial outline.
Design
There were 3 cue-types (Arrows, Eyes, Faces), each in 3 separate blocks. The order of the blocks remained fixed among subjects. (The order was not counterbalanced in this study, due to the limited number of amygdala subjects. However, approximately 1 year after this experiment, Cases 1 and 3 were retested with different order [Case 1: Faces, Eyes, Arrows; Case 3: Eyes, Faces, Arrows]. Analyses of variance [ANOVAs] revealed no interaction of order on cue-type or congruency, nor a 3-way interaction, in both cases [all Fs < 1].) Within each block, cue-target SOAs (100, 300, 700 ms), cue-target relations (congruent, incongruent, neutral), and target locations (right, left) were randomly selected with equal probability to make up a nonpredictive, spatially cued, target detection test. Ten catch trials where no target followed the cue were randomly dispersed within each block.
Procedure
Participants sat 45 cm from the monitor. Subjects were instructed to maintain fixation throughout each trial, and upon target detection, to press the spacebar on the keyboard with their dominant index finger. The nature of the cue stimuli (e.g., the resemblance thereof to eyes or arrows) was never mentioned, nor was the probability in relation to cue-target congruency. Fifteen practice trials were given before each block. The RT from the onset of the target, to the pressing of the key was recorded. Time out was set at 1500 ms, with an interstimulus interval of 3000 ms. A total of 190 trials comprised one block, which took approximately 15 min to complete. Subjects were given a minimum of 10 min between blocks to rest. Eye movements were not monitored for the control subjects, for it has been confirmed in a number of studies that normal subjects reliably do not move their eyes on similar experiments (Posner 1980; Friesen and Kingstone 2003; Friesen et al. 2004). Amygdala subjects were monitored for eye movements by direct viewing of the experimenter, and all were able to maintain fixation almost all the time. (In the retesting session mentioned in previous section, eye movements of Cases 1 and 3 were monitored using an infrared pupil–corneal reflection eye movement monitoring system [Eyemark Recorder 8B model ST-650, nac Image Technology Inc., Tokyo, Japan]. Case 1 demonstrated only one eye movement in the Eyes block. Case 3 demonstrated eye movements in 7, 5, and 8 trials for Eyes, Faces, and Arrows, respectively, comprising 3.3% of the entire experiment. All eye movements were detected in the target display. There was no fixation failure in the fixation display, or in the cue display.)
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Results |
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Errors, defined as anticipations (RTs < 100 ms), RTs longer than 1000 ms, time outs (no response), and incorrect responses (pressing a key other than the correct spacebar), were first discarded from further analysis, which eliminated less than 1% of both amygdala and normal data. The mean RTs and standard deviations (SDs) of all trials for both groups are presented in Table 3. The mean RTs as a function of congruency and SOA are shown for each cue-type, for each group in Figure 3.
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Raw RTs were then submitted to ANOVA with a between-subject variable of group (amygdala, normal), and within-subject variables of cue-type (Arrows, Eyes, Faces), cue-target congruency (congruent, incongruent, neutral), and SOA (100, 300 and 700 ms). The main effects of congruency (F2,18 = 9.49, P < 0.001) and SOA (F2,18 = 12.43, P < 0.001) were significant. The main effect of group approached significance (F1,18 = 3.51, P = 0.077). The critical group x cue-type x congruency interaction was significant (F4,18 = 3.18, P = 0.018). Post hoc analysis of this interaction revealed that the congruency effect was significant for all cue-types for the controls (Arrows; F2,14 = 9.58, P < 0.001, Eyes; F2,14 = 8.01, P < 0.001, Faces; F2,14 = 5.25, P = 0.007), whereas the amygdala group showed a significant congruency effect only for Arrows (F2,4 = 7.24, P = 0.001), and not for the 2 gaze cues (Eyes; F2,4 = 0.29, P = 0.751, Faces; F2,4 = 1.16, P = 0.319). To illustrate the critical interaction more clearly, the benefits of congruent cues over incongruent/ neutral cues were determined for each cue-type as RT differences (RT incongruent – RT congruent, and RT neutral – RT congruent) and were calculated for each individual. They were averaged within groups and are illustrated in Figure 4. In sum, unilateral amygdala-damaged subjects demonstrated a distinctive difference from the normal subjects in that their response is differentially facilitated by congruent arrow cues but not by congruent gaze cues. Other significant interactions were cue-type x congruency (F4,18 = 4.45, P = 0.003) (diminished congruency effect for Faces), and cue-type x SOA (F4,18 = 3.78, P = 0.008) (less SOA effect for Faces).
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Subsequently, within-group analyses of laterality effects were conducted for the amygdala group. The simple effect of lesion side (right, left) proved to be nonsignificant using ANOVA (F1,3 = 1.77, P = 0.276). Then all performance was regrouped in reference to lesion side. First, an ANOVA was conducted with cue-side (in reference to lesion; ipsilesional, contralesional) and congruency (congruent, incongruent) as the variables, which revealed neither a significant main effect of cue-side (F1,4 = 0.36, P = 0.583) nor a significant interaction (F1,4 = 1.22, P = 0.332) (note that neutral cues were not included in this analysis because they would automatically predict neutral trials). Second, an ANOVA was conducted with target-side (in reference to lesion; ipsilesional, contralesional) and congruency (congruent, incongruent, neutral) as the variable, which also revealed neither a significant main effect of target-side (F1,4 = 1.18, P = 0.339) nor a significant interaction (F2,4 = 0.24, P = 0.791). In sum, based on the very limited number of unilateral amygdala cases in this study, no laterality effect was delineated.
Finally, in an attempt to investigate whether the extent of amygdala lesion might correlate with the behavioral benefit derived from congruent cues, MRIs of amygdala cases were reviewed by 2 independent radiologists with close scrutiny, and the lesions were consistently ranked from the least extensive (1), to the most extensive (5). When both benefit differences (RT incongruent – RT congruent and RT neutral – RT congruent) for all blocks were grouped together, we observed a Spearman's rank correlation coefficient of –0.274 (P = 0.143), which might be tentatively suggestive of a very weak trend for a negative correlation between the extent of amygdala damage and benefit. Nevertheless, when regrouped according to benefit types (benefit over incongruent or neutral trials), or according to blocks (Arrows, Eyes, Faces), the correlation did not approach significance.
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Discussion |
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In this report, we have demonstrated in a group of unilateral amygdala-damaged subjects, a robust deficit in attentional orienting triggered by gaze direction, in the face of a relatively normal orienting to arrow direction. This is evidence for the selective role that the amygdala plays in detecting and analyzing significant social stimuli, and orienting attention accordingly. Such function, when damaged, might underpin many of the intriguing impairments identified in a number of amygdala-damaged subjects. Namely, the aforementioned impairment in recognizing fearful faces (Adolphs et al. 1994
, 1999), the difficulty in discriminating gaze direction (Young et al. 1995; Broks et al. 1998), the misjudgment of trustworthiness and approachability from unfavorable faces (Adolphs et al. 1998), and the impairment of making fixations on eyes (Adolphs et al. 2005) might all be attributed, at least in part, to a common fundamental deficit in exploring for a relevant social signal, allocating attention to it, extracting the critical feature, and guiding behavior accordingly. Our findings also converge with the neuroimaging data (Morris et al. 1998; Whalen et al. 1998; Morris et al. 2001; Vuilleumier et al. 2001) to implicate the involvement of the amygdala in covert attention allocated to significant social stimuli.
The current study answers in the affirmative to the outstanding question of whether the social (or biological) valence of a stimulus (e.g., eyes opposed to arrow signs) is critical for amygdala involvement. In close resemblance is the finding from a case with a lesion to the right superior temporal sulcus (STS) area, where biological motion processing is often implicated (Bonda et al. 1996; Puce et al. 1998; Pelphrey et al. 2003; Akiyama, Kato, Muramatsu, Saito, Nakachi, et al. 2006). This patient also demonstrated a deficit in gaze-triggered orienting in the face of an intact arrow-triggered orienting (Akiyama, Kato, Muramatsu, Saito, Umeda, et al. 2006). The similar findings from the 2 studies implicate that the amygdala and the STS might work in concert to selectively process significant social stimuli such as eyes. The amygdala, where very rapid, but coarse information enters (Morris et al. 1999; Vuilleumier et al. 2003), might be in the position to detect potential social stimulus, and crudely evaluate its significance. Through its reciprocal connections with the STS (Amaral et al. 1992; Freese and Amaral 2005), the amygdala might then relay potentially significant biological stimuli to the STS for finer analysis. Indeed, a recent study (Vuilleumier et al. 2004) reported that the extent of amygdala damage negatively correlated with the enhancement of fusiform and STS activation shown for fearful over neutral faces, suggesting the projection of activation from the amygdala in response to significant biological stimuli.
On the other hand, a considerable amount of literature suggests that the function of the amygdala might not be limited to a strictly social extent, but might extend to the detection of arousing, goal-relevant stimuli in general (Ochsner 2004; Sander et al. 2005). For example, learned predictive cues that guide goal-directed behavior have been shown to be dependent on the amygdala to be effectively utilized; rats with lesions to the central nucleus of the amygdala demonstrate decreased orienting responses toward cues (light), which reliably predict a significant event (food) (Holland and Gallagher 1999; Lee et al. 2005). Interestingly, attention to the target event (food) itself was uncompromised in these rats, implicating a specific deficit in attending to cues. Also in humans, there is growing evidence for the role of the amygdala, in conjunction with the prefrontal cortex, to compute the predictive value of a stimulus (Whalen et al. 2001; Kahn et al. 2002; Kim et al. 2003). Moreover, the human amygdala is considered to be critically involved in relevance detection, where not only social but motivational self-relevant stimuli are rapidly detected from the environment, allowing efficient orienting of processing resources toward salient events (Sander et al. 2005). In this line, there is a possibility that an arrow sign, which is inherently coupled with the expectation for an important value or stimulus in its alignment might also "capture the amygdala's attention" to an extent. Although the results of the present study demonstrated no significant group differences in the congruency effect for Arrows, the amygdala group did show a nonsignificant reduction of congruency benefit for Arrows (Fig. 4). It could thus be tentatively suggested that unilateral amygdala damage preferentially hampers gaze-triggered orienting but might also affect arrow-triggered orienting very subtly.
In the field of functional neuroimaging, there is an on-going debate over the extent to which attentional factors modulate amygdala activation generated by fearful stimuli in the normal brain. On one hand, the amygdala seems to demonstrate automatic involvement to fearful faces, as evidenced by its activation even when the fearful face is outside the focus of attention (e.g., Morris et al. 1998, 2001; Vuilleumier et al. 2001; Anderson et al. 2003). On the other hand, there are also a number of studies that conflict with this view. Pessoa et al. (2002, 2005) have demonstrated that when competing tasks consume much of the attentional resources, the unattended fearful faces fail to activate the amygdala, thereby arguing against the automatic nature of amygdala involvement. Bishop et al. (2004) have reported that the state anxiety of individuals might be a determining factor of whether unattended fearful faces are captured by the amygdala; high-anxious subjects demonstrated left amygdala activation to both attended and unattended fearful faces, whereas subjects with low anxiety demonstrated differential activation in the left amygdala to attended, over unattended fearful faces. Although the primary purpose of this present report was not aimed at clarifying these discrepancies, it might nonetheless shed some light onto this interesting debate. Our results studying amygdala-damaged subjects, along with Adolphs et al.'s (2005) results, do suggest that bilaterally intact amygdala is essential in efficiently guiding attention according to the social stimuli it receives. It might thus be more correctly stated that amygdala activation modulates attention. In this view, amygdala activation might be reflective of the allocation of attention to significant, self-relevant stimuli.
The patient group of autism, whose lack in reciprocal gaze exchange is one of the cardinal manifestations (American Psychiatric Association 1994), and whose amygdala have been reported to be anatomically (Kemper and Bauman 1993, 1998; Courchesne 1997; Howard et al. 2000; Sparks et al. 2002) and functionally (Baron-Cohen et al. 1999; Pierce et al. 2001; Castelli et al. 2002) aberrant, have previously been studied with similar spatial cueing tasks. Senju et al. (2004) have reported that autistic children demonstrated a relatively normal gaze and arrow effect in a nonpredictive condition but their performance was quite aberrant when the condition was counterpredictive. Ristic et al. (2005) reported in a group of autistic children, a relatively normal gaze effect in a predictive condition but absent gaze effect in a nonpredictive condition. The 2 studies indicate a decrease in attentional orienting triggered by gaze in autistic children, similar to (but to a lesser extent than) the amygdala-damaged subjects in the current study. Taken together, properly functioning amygdala might be essential to normal attentional orienting triggered by gaze, and perhaps in a wider scope, to normal gaze behavior such as eye-contact and gaze-following.
In the present study, we have used 2 gaze stimuli; eyes with and without a facial outline. The 2 did not differentiate from one another in performance for both normal and amygdala groups; normal controls showed significant congruency effects for both gaze cues, and the amygdala subjects showed no such effect for either cue. This finding is in concordance with prior studies demonstrating that the mere eyes (or even eye-whites) of a frightened face is equally sufficient in activating the amygdala (Morris et al. 2002; Whalen et al. 2004) as the entire frightened face. Of note, the Face condition in our experiment was devoid of emotional expression, and so the present 2 gaze cues were essentially equivalent in their emotional valence. When taking into account the finding that gaze direction and facial expression interact when activating the amygdala (Adams et al. 2003; Holmes et al. 2006), and that facial expression modulates attentional orienting triggered by gaze cues (Holmes et al. 2006), future studies might also incorporate different emotional expressions in similar tasks to investigate if the modulation of expression on the gaze effect might differ between the 2 groups.
The major limitation of this study, which is the small number of amygdala cases leaves many unanswered questions to be addressed. Namely, the effect of bilateral amygdala lesions, the comparison of right versus left amygdala lesions with more cases, and the effect of gender on the performance of the amygdala group in similar tasks would be of importance. The comparison of early (congenital to perinatal) versus late amygdala lesion, and possibly a direct comparison with a group of autistic spectrum subjects might also afford fruitful insight into the function of the amygdala. Another limitation is the lack of accurate lesion volumetry in this study. The volumetric analysis of amygdala lesions, along with increased number of cases should yield further interesting findings in the future. The newly identified function of the amygdala, of directing one's "visual system to seek out, fixate, pay attention to and make use of" the sought information, as pointed out by Adolphs et al. (2005), might open new windows to our understanding of attentional, emotional, and social processes of the brain.
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Acknowledgments |
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This work has been partially supported by a Grant-in-Aid for Scientific Research on Priority Areas "Emergence of Adaptive Motor Function through Interaction between Body, Brain and Environment" from the Japanese Ministry of Education, Culture, Sports, Science and Technology to M.K. Conflict of Interest: None declared.
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