Abstract

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.

Introduction

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.

Materials and Methods

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.

Figure 1.

MRI of cases 1–5 (ae, respectively), each depicting a lesion in the unilateral (cases 1 and 2, right; cases 3–5, left) amygdala.

Figure 1.

MRI of cases 1–5 (ae, respectively), each depicting a lesion in the unilateral (cases 1 and 2, right; cases 3–5, left) amygdala.

Table 1

Demographic data

 Amygdala group Normal group 
 Case 1 (N = 15) 
Age 48 40 59 28 42 45.0 ± 9.1 
Gender M 12, F 3 
Handedness R 14, L 1 
Education (years) 12 14 13 16 16 15.5 ± 2.4 
Etiology of lesion Trauma Encephalitis Encephalitis Hemangioma, postsurgery Astrocytoma, postsurgery  
Side of lesion  
Duration of lesion (years) 31  
Medication (mg) V400 None C1.5, Z200 V400 V800, PH 200, PB90  
Wechsler adult intelligence scale-revised       
    Verbal IQ 97 123 86 112 79  
    Performance IQ 91 91 84 98 88  
    Full IQ 94 110 84 106 81  
WMS-R       
    Verbal memory 82 104 86 74 105  
    Visual memory 87 106 95 99 106  
    General memory 82 105 88 77 106  
    Delayed recall 71 99 80 93 110  
    Attention/concentration 112 113 115 113 108  
 Amygdala group Normal group 
 Case 1 (N = 15) 
Age 48 40 59 28 42 45.0 ± 9.1 
Gender M 12, F 3 
Handedness R 14, L 1 
Education (years) 12 14 13 16 16 15.5 ± 2.4 
Etiology of lesion Trauma Encephalitis Encephalitis Hemangioma, postsurgery Astrocytoma, postsurgery  
Side of lesion  
Duration of lesion (years) 31  
Medication (mg) V400 None C1.5, Z200 V400 V800, PH 200, PB90  
Wechsler adult intelligence scale-revised       
    Verbal IQ 97 123 86 112 79  
    Performance IQ 91 91 84 98 88  
    Full IQ 94 110 84 106 81  
WMS-R       
    Verbal memory 82 104 86 74 105  
    Visual memory 87 106 95 99 106  
    General memory 82 105 88 77 106  
    Delayed recall 71 99 80 93 110  
    Attention/concentration 112 113 115 113 108  

Note: V, sodium valproate; C, clonazepam; Z, zonisamide; PH, phenytoin; PB, phenobarbital.

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.

Table 2

Performance on conventional attentional and visuomotor tests

 Amygdala group Control group 
 Case 1 (N = 15) 
Age 48 40 59 28 42 42.3 ± 5.6 
Cancellation Test (%)       
    “3” 100 100 99.1 99.1 100 99.6 ± 0.6 
    “ka” 98.2 99.1 97.4 97.4 99.1 97.6 ± 2.4 
Tapping Span Test       
    Forward 6.3 ± 1.3 
    Backward 5.9 ± 1.4 
SDMT (% achieved) 55.5 61.8 54.5 60.0 60.9 58.4 ± 8.3 
 Amygdala group Control group 
 Case 1 (N = 15) 
Age 48 40 59 28 42 42.3 ± 5.6 
Cancellation Test (%)       
    “3” 100 100 99.1 99.1 100 99.6 ± 0.6 
    “ka” 98.2 99.1 97.4 97.4 99.1 97.6 ± 2.4 
Tapping Span Test       
    Forward 6.3 ± 1.3 
    Backward 5.9 ± 1.4 
SDMT (% achieved) 55.5 61.8 54.5 60.0 60.9 58.4 ± 8.3 

Note: This control group is different from the experimental control group.

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.

Figure 2.

Illustration of the trial sequence in the experiment. A fixation display was presented for 675 ms, followed by a cue display, which was either arrow or gaze (Eyes, Face) direction. The cue was displayed for 100, 300, or 700 ms, then a target was presented, either to the right or left of the cue, and irrespective of cue direction.

Figure 2.

Illustration of the trial sequence in the experiment. A fixation display was presented for 675 ms, followed by a cue display, which was either arrow or gaze (Eyes, Face) direction. The cue was displayed for 100, 300, or 700 ms, then a target was presented, either to the right or left of the cue, and irrespective of cue direction.

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° × 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° × 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.)

Results

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.

Figure 3.

Results of the experiment. The mean RTs of the amygdala group (AM; lines) and normal controls (NC; dotted lines) for each cue-type, as a function of cue-target congruency and SOA length.

Figure 3.

Results of the experiment. The mean RTs of the amygdala group (AM; lines) and normal controls (NC; dotted lines) for each cue-type, as a function of cue-target congruency and SOA length.

Table 3

Results

 Amygdala group Normal group 
Condition RT SD RT SD 
Arrows     
    SOA 100 ms     
        Congruent 414 93 366 78 
        Incongruent 414 78 372 69 
        Neutral 432 91 379 69 
    SOA 300 ms     
        Congruent 379 84 323 65 
        Incongruent 392 73 355 77 
        Neutral 395 76 350 72 
    SOA 700 ms     
        Congruent 366 61 338 75 
        Incongruent 373 62 355 78 
        Neutral 378 79 356 85 
Eyes     
    SOA 100 ms     
        Congruent 415 81 350 60 
        Incongruent 413 84 371 78 
        Neutral 416 87 362 65 
    SOA 300 ms     
        Congruent 384 87 321 56 
        Incongruent 393 75 340 67 
        Neutral 384 81 343 71 
    SOA 700 ms     
        Congruent 383 69 335 75 
        Incongruent 387 68 350 70 
        Neutral 386 68 348 76 
Faces     
    SOA 100 ms     
        Congruent 420 89 345 73 
        Incongruent 420 95 352 63 
        Neutral 408 85 353 72 
    SOA 300 ms     
        Congruent 395 74 320 73 
        Incongruent 396 87 332 68 
        Neutral 400 98 341 83 
    SOA 700 ms     
        Congruent 394 83 328 65 
        Incongruent 402 97 343 81 
        Neutral 386 78 348 77 
 Amygdala group Normal group 
Condition RT SD RT SD 
Arrows     
    SOA 100 ms     
        Congruent 414 93 366 78 
        Incongruent 414 78 372 69 
        Neutral 432 91 379 69 
    SOA 300 ms     
        Congruent 379 84 323 65 
        Incongruent 392 73 355 77 
        Neutral 395 76 350 72 
    SOA 700 ms     
        Congruent 366 61 338 75 
        Incongruent 373 62 355 78 
        Neutral 378 79 356 85 
Eyes     
    SOA 100 ms     
        Congruent 415 81 350 60 
        Incongruent 413 84 371 78 
        Neutral 416 87 362 65 
    SOA 300 ms     
        Congruent 384 87 321 56 
        Incongruent 393 75 340 67 
        Neutral 384 81 343 71 
    SOA 700 ms     
        Congruent 383 69 335 75 
        Incongruent 387 68 350 70 
        Neutral 386 68 348 76 
Faces     
    SOA 100 ms     
        Congruent 420 89 345 73 
        Incongruent 420 95 352 63 
        Neutral 408 85 353 72 
    SOA 300 ms     
        Congruent 395 74 320 73 
        Incongruent 396 87 332 68 
        Neutral 400 98 341 83 
    SOA 700 ms     
        Congruent 394 83 328 65 
        Incongruent 402 97 343 81 
        Neutral 386 78 348 77 

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 × cue-type × 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 × congruency (F4,18 = 4.45, P = 0.003) (diminished congruency effect for Faces), and cue-type × SOA (F4,18= 3.78, P = 0.008) (less SOA effect for Faces).

Figure 4.

The benefits of congruent over incongruent cues (calculated as RT incongruent − RT congruent), and over neutral cues (RT neutral − RT congruent) are shown for each cue-type, averaged within each group. Error bars indicate the 95% confidence interval.

Figure 4.

The benefits of congruent over incongruent cues (calculated as RT incongruent − RT congruent), and over neutral cues (RT neutral − RT congruent) are shown for each cue-type, averaged within each group. Error bars indicate the 95% confidence interval.

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.

Discussion

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.

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.

References

Adams
RB
Jr
Gordon
HL
Baird
AA
Ambady
N
Kleck
RE
Effects of gaze on amygdala sensitivity to anger and fear faces
Science
 , 
2003
, vol. 
300
 pg. 
1536
 
Adolphs
R
Gosselin
F
Buchanan
TW
Tranel
D
Schyns
P
Damasio
AR
A mechanism for impaired fear recognition after amygdala damage
Nature
 , 
2005
, vol. 
433
 (pg. 
68
-
72
)
Adolphs
R
Tranel
D
Damasio
AR
The human amygdala in social judgment
Nature
 , 
1998
, vol. 
393
 (pg. 
470
-
474
)
Adolphs
R
Tranel
D
Damasio
H
Damasio
A
Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala
Nature
 , 
1994
, vol. 
372
 (pg. 
669
-
672
)
Adolphs
R
Tranel
D
Hamann
S
Young
AW
Calder
AJ
Phelps
EA
Anderson
A
Lee
GP
Damasio
AR
Recognition of facial emotion in nine individuals with bilateral amygdala damage
Neuropsychologia
 , 
1999
, vol. 
37
 (pg. 
1111
-
1117
)
Akiyama
T
Kato
M
Muramatsu
T
Saito
F
Nakachi
R
Kashima
H
A deficit in discriminating gaze direction in a case with right superior temporal gyrus lesion
Neuropsychologia
 , 
2006
, vol. 
44
 (pg. 
161
-
170
)
Akiyama
T
Kato
M
Muramatsu
T
Saito
F
Umeda
S
Kashima
H
Gaze but not arrows: a dissociative impairment after right superior temporal gyrus damage
Neuropsychologia
 , 
2006
, vol. 
44
 (pg. 
1804
-
1810
)
Amaral
DG
Price
JL
Pitkanen
A
Carmichael
ST
Aggleton
JP
Anatomical organization of the priamte amygdaloid complex
The amygdala: neurobiological aspects of emotion, memory and mental dysfunction
 , 
1992
New York
Wiley-Liss
(pg. 
1
-
66
)
American Psychiatric Association
Diagnostic and statistical manual of mental disorders
1994
4th ed
Washington (DC)
American Psychiatric Press
Anderson
AK
Christoff
K
Panitz
D
De Rosa
E
Gabrieli
JD
Neural correlates of the automatic processing of threat facial signals
J Neurosci
 , 
2003
, vol. 
23
 (pg. 
5627
-
5633
)
Anderson
AK
Phelps
EA
Lesions of the human amygdala impair enhanced perception of emotionally salient events
Nature
 , 
2001
, vol. 
411
 (pg. 
305
-
309
)
Baron-Cohen
S
Ring
HA
Wheelwright
S
Bullmore
ET
Brammer
MJ
Simmons
A
Williams
SC
Social intelligence in the normal and autistic brain: an fMRI study
Eur J Neurosci
 , 
1999
, vol. 
11
 (pg. 
1891
-
1898
)
Bishop
SJ
Duncan
J
Lawrence
AD
State anxiety modulation of the amygdala response to unattended threat-related stimuli
J Neurosci
 , 
2004
, vol. 
24
 (pg. 
10364
-
10368
)
Bonda
E
Petrides
M
Ostry
D
Evans
A
Specific involvement of human parietal. systems and the amygdala in the perception of biological motion
J Neurosci
 , 
1996
, vol. 
16
 (pg. 
3737
-
3744
)
Broks
P
Young
AW
Maratos
EJ
Coffey
PJ
Calder
AJ
Isaac
CL
Mayes
AR
Hodges
JR
Montaldi
D
Cezayirli
E
, et al.  . 
Face processing impairments after encephalitis: amygdala damage and recognition of fear
Neuropsychologia
 , 
1998
, vol. 
36
 (pg. 
59
-
70
)
Brothers
L
Ring
B
Mesial temporal neurons in the macaque monkey with responses selective for aspects of social stimuli
Behav Brain Res
 , 
1993
, vol. 
57
 (pg. 
53
-
61
)
Castelli
F
Frith
C
Happe
F
Frith
U
Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes
Brain
 , 
2002
, vol. 
125
 (pg. 
1839
-
1849
)
Courchesne
E
Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism
Curr Opin Neurobiol
 , 
1997
, vol. 
7
 (pg. 
269
-
278
)
Freese
JL
Amaral
DG
The organization of projections from the amygdala to visual cortical areas TE and V1 in the macaque monkey
J Comp Neurol
 , 
2005
, vol. 
486
 (pg. 
295
-
317
)
Friesen
CK
Kingstone
A
The eyes have it! Reflexive orienting is triggered by nonpredictive gaze
Psychon Bull Rev
 , 
1998
, vol. 
5
 (pg. 
490
-
495
)
Friesen
CK
Kingstone
A
Covert and overt orienting to gaze direction cues and the effects of fixation offset
Neuroreport
 , 
2003
, vol. 
14
 (pg. 
489
-
493
)
Friesen
CK
Ristic
J
Kingstone
A
Attentional effects of counterpredictive gaze and arrow cues
J Exp Psychol Hum Percept Perform
 , 
2004
, vol. 
30
 (pg. 
319
-
329
)
George
N
Driver
J
Dolan
RJ
Seen gaze-direction modulates fusiform activity and its coupling with other brain areas during face processing
Neuroimage
 , 
2001
, vol. 
13
 (pg. 
1102
-
1112
)
Holland
PC
Gallagher
M
Amygdala circuitry in attentional and representational processes
Trends Cogn Sci
 , 
1999
, vol. 
3
 (pg. 
65
-
73
)
Holmes
A
Richards
A
Green
S
Anxiety and sensitivity to eye gaze in emotional faces
Brain Cogn
 , 
2006
, vol. 
60
 (pg. 
282
-
294
)
Hooker
CI
Paller
KA
Gitelman
DR
Parrish
TB
Mesulam
MM
Reber
PJ
Brain networks for analyzing eye gaze
Brain Res Cogn Brain Res
 , 
2003
, vol. 
17
 (pg. 
406
-
418
)
Howard
MA
Cowell
PE
Boucher
J
Broks
P
Mayes
A
Farrant
A
Roberts
N
Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism
Neuroreport
 , 
2000
, vol. 
11
 (pg. 
2931
-
2935
)
Kahn
I
Yeshurun
Y
Rotshtein
P
Fried
I
Ben-Bashat
D
Hendler
T
The role of the amygdala in signaling prospective outcome of choice
Neuron
 , 
2002
, vol. 
33
 (pg. 
983
-
994
)
Kawashima
R
Sugiura
M
Kato
T
Nakamura
A
Hatano
K
Ito
K
Fukuda
H
Kojima
S
Nakamura
K
The human amygdala plays an important role in gaze monitoring. A PET study
Brain
 , 
1999
, vol. 
122
 
Pt 4
(pg. 
779
-
783
)
Kemper
TL
Bauman
ML
The contribution of neuropathologic studies to the understanding of autism
Neurol Clin
 , 
1993
, vol. 
11
 (pg. 
175
-
187
)
Kemper
TL
Bauman
ML
Neuropathology of infantile autism
J Neuropathol Exp Neurol
 , 
1998
, vol. 
57
 (pg. 
645
-
652
)
Kim
H
Somerville
LH
Johnstone
T
Alexander
AL
Whalen
PJ
Inverse amygdala and medial prefrontal cortex responses to surprised faces
Neuroreport
 , 
2003
, vol. 
14
 (pg. 
2317
-
2322
)
Krolak-Salmon
P
Henaff
MA
Vighetto
A
Bertrand
O
Mauguiere
F
Early amygdala reaction to fear spreading in occipital, temporal, and frontal cortex: a depth electrode ERP study in human
Neuron
 , 
2004
, vol. 
42
 (pg. 
665
-
676
)
Lee
HJ
Groshek
F
Petrovich
GD
Cantalini
JP
Gallagher
M
Holland
PC
Role of amygdalo-nigral circuitry in conditioning of a visual stimulus paired with food
J Neurosci
 , 
2005
, vol. 
25
 (pg. 
3881
-
3888
)
Morris
JS
deBonis
M
Dolan
RJ
Human amygdala responses to fearful eyes
Neuroimage
 , 
2002
, vol. 
17
 (pg. 
214
-
222
)
Morris
JS
DeGelder
B
Weiskrantz
L
Dolan
RJ
Differential extrageniculostriate and amygdala responses to presentation of emotional faces in a cortically blind field
Brain
 , 
2001
, vol. 
124
 (pg. 
1241
-
1252
)
Morris
JS
Frith
CD
Perrett
DI
Rowland
D
Young
AW
Calder
AJ
Dolan
RJ
A differential neural response in the human amygdala to fearful and happy facial expressions
Nature
 , 
1996
, vol. 
383
 (pg. 
812
-
815
)
Morris
JS
Ohman
A
Dolan
RJ
Conscious and unconscious emotional learning in the human amygdala
Nature
 , 
1998
, vol. 
393
 (pg. 
467
-
470
)
Morris
JS
Ohman
A
Dolan
RJ
A subcortical pathway to the right amygdala mediating “unseen” fear
Proc Natl Acad Sci USA
 , 
1999
, vol. 
96
 (pg. 
1680
-
1685
)
Nomura
M
Ohira
H
Haneda
K
Iidaka
T
Sadato
N
Okada
T
Yonekura
Y
Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study
Neuroimage
 , 
2004
, vol. 
21
 (pg. 
352
-
363
)
Ochsner
KN
Current directions in social cognitive neuroscience
Curr Opin Neurobiol
 , 
2004
, vol. 
14
 (pg. 
254
-
258
)
Pelphrey
KA
Singerman
JD
Allison
T
McCarthy
G
Brain activation evoked by perception of gaze shifts: the influence of context
Neuropsychologia
 , 
2003
, vol. 
41
 (pg. 
156
-
170
)
Pessoa
L
McKenna
M
Gutierrez
E
Ungerleider
LG
Neural processing of emotional faces requires attention
Proc Natl Acad Sci USA
 , 
2002
, vol. 
99
 (pg. 
11458
-
11463
)
Pessoa
L
Padmala
S
Morland
T
Fate of unattended fearful faces in the amygdala is determined by both attentional resources and cognitive modulation
Neuroimage
 , 
2005
, vol. 
28
 (pg. 
249
-
255
)
Pierce
K
Muller
RA
Ambrose
J
Allen
G
Courchesne
E
Face processing occurs outside the fusiform ‘face area’ in autism: evidence from functional MRI
Brain
 , 
2001
, vol. 
124
 (pg. 
2059
-
2073
)
Posner
MI
Orienting of attention
Q J Exp Psychol
 , 
1980
, vol. 
32
 (pg. 
3
-
25
)
Puce
A
Allison
T
Bentin
S
Gore
JC
McCarthy
G
Temporal cortex activation in humans viewing eye and mouth movements
J Neurosci
 , 
1998
, vol. 
18
 (pg. 
2188
-
2199
)
Ristic
J
Mottron
L
Friesen
CK
Iarocci
G
Burack
JA
Kingstone
A
Eyes are special but not for everyone: the case of autism
Brain Res Cogn Brain Res
 , 
2005
, vol. 
24
 (pg. 
715
-
718
)
Sander
D
Grandjean
D
Scherer
KR
A systems approach to appraisal mechanisms in emotion
Neural Netw
 , 
2005
, vol. 
18
 (pg. 
317
-
352
)
Senju
A
Tojo
Y
Dairoku
H
Hasegawa
T
Reflexive orienting in response to eye gaze and an arrow in children with and without autism
J Child Psychol Psychiatry
 , 
2004
, vol. 
45
 (pg. 
445
-
458
)
Sparks
BF
Friedman
SD
Shaw
DW
Aylward
EH
Echelard
D
Artru
AA
Maravilla
KR
Giedd
JN
Munson
J
Dawson
G
, et al.  . 
Brain structural abnormalities in young children with autism spectrum disorder
Neurology
 , 
2002
, vol. 
59
 (pg. 
184
-
192
)
Tipples
J
Eye gaze is not unique: automatic orienting in response to uninformative arrows
Psychon Bull Rev
 , 
2002
, vol. 
9
 (pg. 
314
-
318
)
Vuilleumier
P
Armony
JL
Driver
J
Dolan
RJ
Effects of attention and emotion on face processing in the human brain: an event-related fMRI study
Neuron
 , 
2001
, vol. 
30
 (pg. 
829
-
841
)
Vuilleumier
P
Armony
JL
Driver
J
Dolan
RJ
Distinct spatial frequency sensitivities for processing faces and emotional expressions
Nat Neurosci
 , 
2003
, vol. 
6
 (pg. 
624
-
631
)
Vuilleumier
P
Richardson
MP
Armony
JL
Driver
J
Dolan
RJ
Distant influences of amygdala lesion on visual cortical activation during emotional face processing
Nat Neurosci
 , 
2004
, vol. 
7
 (pg. 
1271
-
1278
)
Whalen
PJ
Kagan
J
Cook
RG
Davis
FC
Kim
H
Polis
S
McLaren
DG
Somerville
LH
McLean
AA
Maxwell
JS
, et al.  . 
Human amygdala responsivity to masked fearful eye whites
Science
 , 
2004
, vol. 
306
 pg. 
2061
 
Whalen
PJ
Rauch
SL
Etcoff
NL
McInerney
SC
Lee
MB
Jenike
MA
Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge
J Neurosci
 , 
1998
, vol. 
18
 (pg. 
411
-
418
)
Whalen
PJ
Shin
LM
McInerney
SC
Fischer
H
Wright
CI
Rauch
SL
A functional MRI study of human amygdala responses to facial expressions of fear versus anger
Emotion
 , 
2001
, vol. 
1
 (pg. 
70
-
83
)
Williams
MA
Morris
AP
McGlone
F
Abbott
DF
Mattingley
JB
Amygdala responses to fearful and happy facial expressions under conditions of binocular suppression
J Neurosci
 , 
2004
, vol. 
24
 (pg. 
2898
-
2904
)
Young
AW
Aggleton
JP
Hellawell
DJ
Johnson
M
Broks
P
Hanley
JR
Face processing impairments after amygdalotomy
Brain
 , 
1995
, vol. 
118
 
Pt 1
(pg. 
15
-
24
)