پاسخ عصبی دیفرانسیل به حالات چهره منفی تهدید آمیز و غیر تهدید کننده در افراد اسکیزوفرنی پارانوئید و غیر پارانوئید

Abstract Several studies have demonstrated impaired facial expression recognition in schizophrenia. Few have examined the neural basis for this; none have compared the neural correlates of facial expression perception in different schizophrenic patient subgroups. We compared neural responses to facial expressions in 10 right-handed schizophrenic patients (five paranoid and five non-paranoid) and five normal volunteers using functional Magnetic Resonance Imaging (fMRI). In three 5-min experiments, subjects viewed alternating 30-s blocks of black-and-white facial expressions of either fear, anger or disgust contrasted with expressions of mild happiness. After scanning, subjects categorised each expression. All patients were less accurate in identifying expressions, and showed less activation to these stimuli than normals. Non-paranoids performed poorly in the identification task and failed to activate neural regions that are normally linked with perception of these stimuli. They categorised disgust as either anger or fear more frequently than paranoids, and demonstrated in response to disgust expressions activation in the amygdala, a region associated with perception of fearful faces. Paranoids were more accurate in recognising expressions, and demonstrated greater activation than non-paranoids to most stimuli. We provide the first evidence for a distinction between two schizophrenic patient subgroups on the basis of recognition of and neural response to different negative facial expressions.

Introduction Faces convey a wealth of personal information, such as identity, expression, age and sex (Bruce and Young, 1986). The ability to recognise the different aspects of each face is crucial for adaptation in the social milieu. Patients with schizophrenia often perform poorly in social situations, appearing to misinterpret social cues and exhibiting poor social skills. Furthermore, delusions often emerge as misinterpretations of social interactions and events, frequently revolving around a person’s relationship to others and role in society rather than neutral or impersonal themes (Brennan and Hemsley, 1984, Bentall et al., 1991 and Bentall et al., 1994). For this reason, perception of facial stimuli and, in particular, perception of facial emotional expressions have been studied frequently in this patient group. Whilst some studies have provided evidence for a generalised performance deficit in facial processing, rather than a specific emotion recognition deficit in schizophrenia (Archer et al., 1992, Kerr and Neale, 1993 and Mueser et al., 1997), many have demonstrated poor judgement of facial emotion in schizophrenic patients (Novic et al., 1984, Feinberg et al., 1986, Gessler et al., 1989 and Gaebel and Woelwer, 1992). A recent study tested patients’ ability to recognise an affect state from audio-visual presentation of facial expression, voice tone and upper body movement cues (Bell et al., 1997). Although schizophrenic patients were generally impaired compared with normal and patient controls, they demonstrated a differential impairment in negative affect recognition. Attempts to differentiate the performance on facial expression recognition tasks of different subgroups of schizophrenic patients have provided evidence for the superior ability of paranoid compared with non-paranoid patients in the labelling of negative affects (Kline et al., 1992). Other recent studies have investigated perception and encoding of facial expressions and postures in the same group of schizophrenic patients (Flack et al., 1997 and Flack et al., 1998). These patients failed to respond normally to postures expected to induce anger and disgust. Taken together, these findings suggest that there is a generalised deficit in facial perception in schizophrenia, but that the deficit may be particularly apparent for negative expressions of emotion and in non-paranoid patients. Although paranoid patients (those with persecutory delusions) might be generally superior to non-paranoid patients in the recognition of negative facial expressions, it is possible that the paranoid individuals have difficulty with specific negative emotions. Given the persecutory content of their delusions, threat-related expressions are of particular relevance. Some studies have shown increased attention to threatening stimuli in this group (Bentall and Kaney, 1989, Kaney et al., 1992, Bentall et al., 1995 and Bentall and Kaney, 1996), while studies of on-line visual appraisal using visual scan paths have suggested avoidance of overtly threatening scenes (Phillips et al., 1999). Paranoid patients may have difficulty in the correct labelling of threat-related negative emotions (fear, anger) displayed by others for any of several reasons, including: 1. identification of threat where none exists; 2. avoidance of thorough appraisal of threat; and 3. a deficit in the ability to correctly label negative emotions. On the other hand, schizophrenic patients without a history of persecutory delusions, but with other symptoms (e.g. passivity experiences or negative symptoms) may have a more generalised cognitive or perceptual deficit in the processing of all facial expressions. Fear and anger are both basic emotions experienced when an individual is under threat (Darwin, 1872/1998, 3rd. edition). Disgust is another negative emotion usually experienced in a food-related context, and is thought to prevent the ingestion of harmful, waste products (Roizin and Fallon, 1987 and Phillips et al., 1998a). The three basic emotions of fear, anger and disgust are characterised by a specific facial expression and an associated behavioural response (Ekman and Friesen, 1976). 1.1. Neurobiology of expression perception Studies of subjects with focal brain lesions and those employing functional neuroimaging techniques with normal volunteers have demonstrated that the perception of fearful facial expressions involves the amygdala (Adolphs et al., 1994, Adolphs et al., 1995, Young et al., 1995, Breiter et al., 1996, Calder et al., 1996, Morris et al., 1996 and Whalen et al., 1998), the perception of angry facial expressions involves orbitofrontal cortex and anterior cingulate (Blair et al., 1999), and the perception of facial expressions of disgust is linked with the anterior insula and striatum (Sprengelmeyer et al., 1996, Phillips et al., 1997 and Phillips et al., 1998b). The perception of negative facial expressions in general appears to involve the inferior frontal cortex (Sprengelmeyer et al., 1998). Amygdalar activation is also evident during perception of sad facial expressions (Blair et al., 1999), during sad mood induction in normal controls (Schneider et al., 1997) and in depressed patients (Abercrombie et al., 1998), but not in schizophrenic patients (Schneider et al., 1998). In the current study, we investigated the neural response to different negative facial expressions in paranoid compared with non-paranoid schizophrenic patients and normal volunteers using functional Magnetic Resonance Imaging (fMRI). Fearful and angry facial expressions were employed as threat-related stimuli, whilst expressions of disgust were employed as expressions of a negative emotion but without overt threat. We predicted that the paranoid schizophrenics would have an abnormal neural response to expressions of fear and anger only, whilst the non-paranoid group would show more pervasive impairments. Specific hypotheses were: 1. All schizophrenic patients would be less accurate in identifying specific facial expressions compared with normals, while paranoid schizophrenics would be more accurate than non-paranoid patients in the identification of expressions of fear and anger, in view of the postulated increased attention to threat-related stimuli in the former. 2. All schizophrenic patients would, in comparison with normal controls, demonstrate reduced activation in the specific regions described above in response to each type of facial expression. 3. Paranoid schizophrenics would show reduced activation in regions normally activated by expressions of fear and anger (amygdala and anterior cingulate/inferior frontal cortex, respectively), but a similar pattern of activation to that of normal subjects in response to facial expressions of disgust (activation in the insula and in regions important for processing salient visual stimuli, including fusiform and lingual gyri, and superior, middle and inferior temporal cortex). 4. Non-paranoid patients would show a more abnormal pattern of activation than paranoid patients in regions normally activated by all three negative facial expressions (no activation of the amygdala, frontal cortex and insula in response to expressions of fear, anger and disgust, respectively).

Results 3.1. Sex decision task accuracy and facial expression ratings In the normal controls, the mean percentage accuracy scores in the sex decision task in each of the three experiments, anger, fear and disgust, were 100, 99 and 99%, respectively (ranges: 98–100%). In the paranoid schizophrenic patients for the three experiments: anger, fear and disgust, the mean percentage accuracy scores were 91.5% (range: 79–100%), 93% (range: 88–98%), and 90% (range: 81–98%), respectively. In the non-paranoid patients, the scores were 73% (range: 43–100%), 84.5% (range: 48–100%), and 97% (range: 90–100%), respectively. There was no significant difference overall in the percentage accuracy scores of the three subject groups in the anger experiment (Kruskal–Wallis Test: χ2=4.28; d.f.=2; P=0.1). The schizophrenic patients were less accurate in judgement of the sex of the facial stimuli in the fear (Kruskal–Wallis Test: chi-squared=5.43; d.f.=2; P=0.07) and disgust (Kruskal–Wallis Test: χ2=7.06; d.f.=2; P=0.03) experiments. There were, however, no significant differences between the two groups of schizophrenic patients in percentage accuracy scores on each of the three experiments (Mann–Whitney U tests: two-tailed P=0.3, 0.8 and 0.1, respectively for the anger, fear and disgust experiments). The mean accuracy ratings for correct identification of expressions of anger, fear and disgust in the paranoid schizophrenics were: 62% (5/8) (range: 25–75%), 75% (6/8) (range: 63–100%) and 75% (6/8) (range: 50–100%), respectively. The mean accuracy ratings in the non-paranoid patients were: 62% (5/8) (range: 14–88%), 50% (4/8) (range: 20–63%), and 62% (5/8) (range: 13–100%), respectively. The paranoid patients had mean accuracy ratings for both the neutral and mildly happy expressions of 62% (5/8) (ranges: 13–100%, and 50–88%, respectively). The mean accuracy ratings for the non-paranoid patients were 75% (6/8) (ranges: 38–100% and 25–100%, respectively) for both of these expressions. The paranoid schizophrenics were more accurate than the non-paranoid schizophrenics in identification of facial expressions of fear and disgust, particularly so for expressions of fear, although, in view of the small numbers of subjects, the differences in accuracy scores between the two groups were not statistically significant. The paranoid patients were less accurate than the non-paranoid patients in the identification of mildly happy and neutral facial expressions. The non-paranoid patients were inaccurate in the identification of all three negative facial expressions. We were interested in the pattern of errors made by the schizophrenic patients, namely, the confusion of each of the three negative expressions with the other two, and also the confusion of mildly (25%) happy and 100% neutral, and 100% neutral with any of the three negative expressions. This would allow us to determine the extent to which the different negative expressions and the two ‘neutrals’ (100% neutral and 25% happy) were distinguished from each other, and the extent to which the three negative expressions and the two ‘neutral’ expressions were confused (see Table 2). Since there were seven different categories of facial expression from which to choose when patients rated the stimuli, chance level of performance was at 1/7 (14.2%), i.e. approximately one of the eight examples of each facial expression categorised correctly per subject, and five in total per patient group. The non-paranoid patients tended to confuse expressions of disgust with anger and fear to a greater extent than the paranoid patients. The paranoid patients tended to confuse mildly (25%) happy with 100% neutral expressions to a greater extent than non-paranoid patients. Neither group of patients confused the three negative expressions with the two ‘neutral’ expressions. Table 2. Responses of the schizophrenic patients in facial expression identificationa Stimuli Response Angry Fear Disgust Neutral Happy Surprise Sad Other Paranoids Angry 24 5 5 1 0 3 2 0 Fear 3 32 0 0 1 3 1 0 Disgust 6 1 29 1 1 1 1 0 Neutral 0 1 0 23 10 0 6 0 Mildly happy 0 0 0 13 25 0 1 1 Total 33 39 34 38 37 7 11 1 Non-paranoids Angry 26 4 4 2 0 3 2 1 Fear 7 18 1 0 0 8 2 4 Disgust 9 3 22 0 1 0 3 2 Neutral 1 1 2 29 5 0 1 1 Mildly happy 0 3 0 8 27 0 1 1 Total 43 29 29 39 33 11 9 9 a Numbers refer to the total number of stimuli identified as depicting each facial expression in the group of five paranoid or five non-paranoid patients. Table options 3.2. Generic brain activation maps 3.2.1. Activation in response to angry contrasted with neutral facial expressions In normal controls, angry expressions activated the inferior frontal gyrus, anterior cingulate gyrus, putamen, superior temporal gyrus, hippocampus, cerebellum and fusiform gyrus, many of these as predicted. Activation in response to neutral expressions (or deactivation in response to the angry expressions) was demonstrated in the cerebellum, superior temporal gyrus, anterior cingulate gyrus, medial frontal gyrus and caudate nucleus (Table 3a and Fig. 2). Table 3. Region (approximate Side x a y a z a No. of P b Condition of Brodmann area) voxels signal increasec (a) Normal controls: generically activated brain regions to angry facial expressions Inferior frontal gyrus (45) R 49 11 4 30 0.00007 Angry Anterior cingulate gyrus (32) R 3 42 −2 16 0.00008 Angry L −23 36 −2 7 0.0002 Angry Putamen L −17 −28 9 11 0.00007 Angry −9 −6 4 9 0.0007 Angry −26 6 −7 9 0.0004 Angry Superior temporal gyrus (38) L −40 11 −7 6 0.0002 Angry Hippocampus L −9 −11 −18 6 0.0003 Angry Cerebellum R 12 −56 −29 5 0.0002 Angry Fusiform gyrus (19) L −38 −64 −13 5 0.0007 Angry Cerebellum L −9 −44 −7 10 0.0004 Neutral −12 −72 −13 6 0.0004 Neutral Superior temporal gyrus (22) R 52 0 −2 8 0.0001 Neutral Anterior cingulate gyrus L −17 44 −2 6 0.0009 Neutral (32/24) −3 28 −2 5 0.0008 Neutral Medial frontal gyrus (10) R 38 39 −2 5 0.0004 Neutral Caudate nucleus L −6 17 −2 5 0.002 Neutral (b) All schizophrenics: generically activated brain regions to angry facial expressions Postcentral gyrus (43) L −52 −11 20 4 0.003 Neutral Hippocampus L −32 −8 −13 3 0.001 Neutral (c) Paranoid schizophrenics: generically activated brain regions to angry facial expressions Postcentral gyrus (43) L −52 −14 20 4 0.005 Angry Inferior frontal gyrus (47) L −26 28 −2 7 0.0006 Neutral Anterior cingulate gyrus (24) L −20 25 −2 3 0.004 Neutral (d) Non-paranoid psychotic patients: generically activated brain regions to angry facial expressions Posterior cingulate gyrus L −3 −50 20 12 0.0007 Angry (30) −6 −47 26 10 0.0007 Angry Inferior temporal gyrus (19) L −38 −58 −2 11 0.00005 Angry Cerebellum L −12 −69 −7 11 0.00003 Angry Thalamus (pulvinar nucleus) L −12 −31 15 7 0.0007 Angry Nucleus accumbens R 9 6 −7 7 0.0003 Neutral a The cluster with the largest number of voxels within each region is reported. Talairach co-ordinates refer to the voxel with the maximum FPQ (fundamental power quotient) in each cluster. b All such voxels were identified by a one-tailed test of the null hypothesis that median FPQ is not determined by experimental design. The probability threshold for activation was PFull-size image (<1 K)0.004. c Signal increase was detected either during presentation of angry or neutral baseline (mildly happy) facial expressions. Table options Full-size image (1206 K) Fig. 2. Generic brain activation (GBAM) in the normal controls (n=5) and all schizophrenic patients (n=10) in response to stimuli depicting facial expressions of anger, fear and disgust (red voxels). Voxels activated in response to the neutral baseline facial expressions (25% happy expressions, or deactivated by the negative facial expressions) in each experiment are colored blue. The probability threshold for activation was P⩽0.004. For the experiment in which facial expressions of anger were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 18 mm (left) and 1.5 mm (right) below the transcallosal plane. For the experiment in which facial expressions of fear were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 12.5 mm (left) and 1.5 mm (right) below the transcallosal plane. For the experiment in which facial expressions of disgust were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 1.5 mm below (left) and at 15 mm above (right) the transcallosal plane. The left side of the brain is shown on the right side of the image, and vice versa. In the normal controls, major regions of activation are shown in the hippocampus, anterior cingulate gyrus (BA 32) in response to expressions of anger, in the hippocampus/amygdala (Hi/Am) in response to expressions of fear, and in the insula (I) and globus pallidus (GP) in response to expressions of disgust. Activations associated with presentation of the neutral baseline expressions (deactivations associated with presentation of negative facial expresions) in all three experiments are shown in the superior temporal gyrus (BA 22), medial frontal gyrus (BA 10) and the caudate nucleus (Ca). In the schizophrenic patients, major regions of activation are shown in the insula (I), middle temporal gyrus (BA 21) and lingual gyrus (BA 19) in response to expressions of disgust. Major areas of activation in response to neutral expressions (deactivation in response to negative expressions) are shown in the middle temporal and fusiform gyri (BA 37). Figure options In all 10 schizophrenic patients overall, there was little significant activation to either angry or neutral expressions (Table 3b and Fig. 2). Activation in response to neutral expressions (or deactivation in response to angry expressions) in the paranoid schizophrenics was shown in the inferior frontal gyrus and anterior cingulate gyrus. There was little activation in response to angry expressions (Table 3c and Fig. 3). Non-paranoid schizophrenics showed activation in the posterior cingulate gyrus, inferior temporal gyrus, cerebellum and thalamus in response to angry expressions, and little activation in response to neutral expressions (deactivation in response to angry expressions; Table 3d and Fig. 3). These results were consistent with the prediction of reduced neural responses in both groups of schizophrenic patients in regions activated by angry expressions in normal subjects. Full-size image (1206 K) Fig. 3. Generic brain activation (GBAM) in the paranoid (n=5) and non-paranoid (n=5) schizophrenic patients in response to stimuli depicting facial expressions of anger, fear and disgust contrasted with the neutral baseline expressions. The coloring of the voxels and probability threshold for activation are as in Fig. 2. For the experiment in which facial expressions of anger were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 12.5 mm (left) and 1.5 mm (right) below the transcallosal plane. For the experiment in which facial expressions of fear were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 12.5 mm (left) and 1.5 mm (right) below the transcallosal plane. For the experiment in which facial expressions of disgust were contrasted with the neutral baseline expressions, two transverse brain slices are shown at 12.5 mm (left) and 15 mm above (right) the transcallosal plane. The left side of the brain is shown on the right side of the image, and vice versa. In the paranoid schizophrenic patients, major regions of activation are shown in the fusiform (BA 37) and lingual (BA 19) gyri in response to expressions of fear, and in the insula (I) in response to expressions of disgust. Activations associated with presentation of the neutral baseline expressions (deactivations associated with the presentation of negative expressions) are shown in the hippocampus (Hi) and inferior frontal gyrus (BA 47). In the non-paranoid patients, major regions of activation are shown in the inferior temporal gyrus (BA 19) in response to expressions of anger, the middle temporal gyrus (BA 21) in response to expressions of fear, and in the amygdala (Am), superior temporal gyrus (BA 42), thalamus (T) and middle temporal gyrus (BA 39) in response to expressions of disgust. Activations associated with presentation of the neutral baseline expressions (deactivations associated with presentation of negative expressions) are shown in the middle temporal gyrus (BA 21). Figure options 3.2.2. Differences in neural response to angry contrasted with neutral facial expressions in schizophrenics vs. normal controls Normal controls showed significantly greater activation compared with all 10 schizophrenic patients in response to angry expressions in the inferior frontal gyrus (Brodmann area, BA, 45), putamen and cerebellum, and significantly greater activation to neutral baseline expressions (deactivation to angry expressions) in the superior temporal gyrus (BA 22), medial frontal gyrus (BA 10) and anterior cingulate gyrus (BA 32) (search volume=183 voxels; P<0.05; expected number of false positive activated voxels=9; observed number of activated voxels=106). No brain regions were activated significantly more in the 10 schizophrenic patients compared with the normal controls, as predicted. 3.2.3. Differences in neural response to angry contrasted with neutral facial expressions in paranoid vs. non-paranoid schizophrenics Non-paranoid schizophrenics showed significantly greater activation compared with paranoid schizophrenics to expressions of anger in the cerebellum, thalamus and inferior temporal gyrus (BA 19) (search volume=78 voxels; P<0.05; number of expected false activated voxels=3; observed number of activated voxels=34). No brain regions were activated significantly more in the paranoid schizophrenics. 3.2.4. Activation in response to fearful contrasted with neutral facial expressions In normal controls, fearful expressions activated the hippocampus/amygdala, the middle temporal gyrus, the superior temporal gyrus, putamen, cerebellum and the inferior frontal gyrus, regions similar to those predicted. Activation in response to neutral expressions (deactivation in response to fearful expressions) was demonstrated in the superior and middle temporal gyri (Table 4a and Fig. 2). In all 10 schizophrenic patients overall, fearful expressions activated the postcentral gyrus and inferior frontal gyrus. Activation in response to neutral expressions (deactivation in response to fearful expressions) was demonstrated in visual areas: the middle temporal gyrus and fusiform gyrus (Table 4b and Fig. 2). Paranoid schizophrenics showed activation in the fusiform gyrus, cerebellum, precentral gyrus and lingual gyrus in response to fearful expressions, but not in the amygdala, as predicted. Activation in response to neutral expressions (deactivation in response to fearful expressions) was demonstrated in the posterior cingulate gyrus (Table 4c and Fig. 3). Non-paranoid schizophrenics showed activation in the middle and superior temporal gyri, but not the amygdala, in response to fearful expressions. Activation in response to neutral expressions (deactivation in response to fearful expressions) was demonstrated in the middle temporal gyrus, fusiform gyrus and cerebellum (Table 4d and Fig. 3). Table 4. Region (approximate Side x a y a z a No. of P b Condition of Brodmann area) voxels signal increasec (a) Normal controls: generically activated brain regions to fearful facial expressions Hippocampus/amygdala L −38 0 −13 20 0.0001 Fearful Middle temporal gyrus (19) L −40 −72 20 15 0.0001 Fearful Superior temporal gyrus (38/)22 R 43 8 −13 6 0.0009 Fearful L −49 11 4 6 0.0005 Fearful Putamen L 29 −14 4 6 0.0003 Fearful Cerebellum R 38 −50 −29 5 0.0007 Fearful Inferior frontal gyrus (45) R 35 28 4 5 0.001 Fearful Superior temporal gyrus (22)/Insula R 40 6 −2 27 0.0002 Neutral Middle temporal gyrus R 46 −14 −13 10 0.0006 Neutral (21/37) R 43 −50 −7 8 0.0002 Neutral L −40 −61 9 7 0.0003 Neutral (b) All schizophrenics: generically activated brain regions to fearful facial expressions Postcentral gyrus (43) L −38 −3 15 13 0.0002 Fearful Inferior frontal gyrus (44) L −35 11 15 4 0.002 Fearful Middle temporal gyrus (37) R 46 −58 −2 7 0.0005 Neutral Fusiform gyrus (37) R 29 −44 −13 7 0.0004 Neutral (c) Paranoid schizophrenics: generically activated brain regions to fearful facial expressions Middle temporal gyrus (37) R 26 −42 −13 16 0.00002 Fearful Cerebellum R 23 −67 −13 16 0.0002 Fearful Pre-central gyrus (4) L −35 0 15 10 0.001 Fearful Lingual gyrus (19) R 26 −56 −2 5 0.001 Fearful Posterior cingulate gyrus L −20 −53 9 6 0.0002 Neutral (29/30) (d) Non-paranoid psychotic patients: generically activated brain regions to fearful facial expressions Middle/superior temporal gyrus (21) R 55 −19 −7 7 0.000008 Fearful Superior temporal gyrus (22) L −52 −50 15 5 0.001 Fearful Middle temporal gyrus (21) L −49 −25 −2 10 0.000008 Neutral Fusiform gyrus (37) L −40 −61 −18 6 0.00002 Neutral Cerebellum L −29 −72 −13 5 0.00002 Neutral a The cluster with the largest number of voxels within each region is reported. Talairach coordinates refer to the voxel with the maximum FPQ (fundamental power quotient) in each cluster. b All such voxels were identified by a one-tailed test of the null hypothesis that median FPQ is not determined by experimental design. The probability threshold for activation was PFull-size image (<1 K)0.004. c Signal increase was detected either during presentation of fearful or neutral baseline (mildly happy) facial expressions. Table options 3.2.5. Differences in neural response to fearful contrasted with neutral facial expressions in schizophrenics vs. normal controls Normal controls showed significantly greater activation compared with all 10 schizophrenic patients in response to fearful expressions in the superior temporal gyrus (BA 22 and 38), amygdala and putamen (search volume=142 voxels; P<0.05; expected number of false positive activated voxels=7; observed number of activated voxels=66). No brain regions were activated significantly more in the 10 schizophrenic patients overall compared with the normal controls. 3.2.6. Differences in neural response to fearful contrasted with neutral facial expressions in paranoid vs. non-paranoid schizophrenics Paranoid schizophrenics showed significantly greater activation compared with non-paranoid schizophrenics in response to fearful expressions in the cerebellum, insula, and visual areas [fusiform gyrus (BA 37) and lingual gyrus (BA 19)]. Activation in response to neutral expressions (deactivation in response to fearful expressions) was demonstrated in the posterior cingulate gyrus (BA 29). Non-paranoid schizophrenics showed significantly greater activation compared with paranoid schizophrenics in response to fearful expressions in regions important for visual processing: the middle temporal gyrus (BA 21) and superior temporal gyrus (BA 22) (search volume=101 voxels; P=0.05; number of expected false activated voxels=5; observed number of activated voxels=71). 3.2.7. Activation in response to facial expressions of disgust contrasted with neutral facial expressions In normal controls, expressions of disgust activated the insula (anterior), as predicted, in addition to the cerebellum and globus pallidus. Activation in response to neutral expressions (deactivation to expressions of disgust) was demonstrated in the superior temporal gyrus, putamen and insula (middle) (Table 5a and Fig. 2). In all 10 schizophrenic patients overall, expressions of disgust activated the insula, cerebellum, and the lingual and middle temporal gyri. Activation in response to neutral expressions (deactivation in response to expressions of disgust) was demonstrated in the putamen (Table 5b and Fig. 2). Paranoid schizophrenics showed activation in the cerebellum and insula (anterior) in response to expressions of disgust, regions similar to those activated by the normal controls in response to these expressions. Activation in response to neutral expressions (deactivation in response to expressions of disgust) was demonstrated in the middle occipital gyrus, transverse temporal gyrus, cerebellum, claustrum, superior temporal gyrus and hippocampus (Table 5c and Fig. 3). Non-paranoid schizophrenics showed activation in the thalamus, anterior cingulate gyrus, postcentral gyrus, areas important for visual processing (superior and middle temporal gyri, and lingual gyrus), and the amygdala, but not the insula, in response to expressions of disgust. Activation in response to neutral expressions (deactivation in response to expressions of disgust) was demonstrated in the fusiform gyrus (Table 5d and Fig. 3). Table 5. Region (approximate Side x a y a z a No. of P b Condition of Brodmann area) voxels signal increasec (a) Normal controls: generically activated brain regions to facial expressions of disgust Cerebellum R 12 −44 −29 8 0.001 Disgust Insula (anterior) L −35 −3 −2 6 0.0001 Disgust Globus pallidus R 14 0 −2 5 0.000008 Disgust Superior temporal gyrus R 29 8 −13 15 0.0004 Neutral (38/22) 52 −8 4 8 0.0004 Neutral Putamen R 23 0 4 6 0.0006 Neutral Insula (middle) R 35 −11 9 5 0.0009 Neutral (b) All schizophrenics: generically activated brain regions to facial expressions of disgust Insula L −26 0 15 10 0.0003 Disgust Cerebellum R 17 −75 −13 10 0.0004 Disgust 35 −53 −13 4 0.003 Disgust Lingual gyrus (19) R 14 −44 −2 9 0.0002 Disgust Middle temporal gyrus (21) R 49 −22 −2 6 0.0009 Disgust Putamen L −32 −11 −2 6 0.0003 Neutral (c) Paranoid schizophrenics: generically activated brain regions to facial expressions of disgust Cerebellum L −9 −58 −13 11 0.00007 Disgust Insula (anterior) L −29 0 15 6 0.002 Disgust Middle occipital gyrus (19) L −29 −78 4 7 0.00007 Neutral Transverse temporal gyrus L −32 −31 9 6 0.0005 Neutral (41) Cerebellum L −9 −61 −18 5 0.002 Neutral Claustrum L −29 0 −7 5 0.0005 Neutral Superior temporal gyrus (22) R 55 −6 9 5 0.0003 Neutral Hippocampus L −29 −39 −2 5 0.0009 Neutral (d) Non-paranoid psychotic patients: generically activated brain regions to facial expressions of disgust Thalamus R 3 −17 15 18 0.00002 Disgust Superior temporal gyrus L −46 −31 9 15 0.00001 Disgust (22/42) R 49 −28 15 6 0.0003 Disgust Anterior cingulate gyrus (32) R 6 47 9 14 0.00001 Disgust Postcentral gyrus (40/43) L −49 −14 15 11 0.0005 Disgust Middle temporal gyrus (39) L −43 −64 15 10 0.0003 Disgust Lingual gyrus (19) R 14 −44 −2 5 0.001 Disgust Amygdala L −20 −8 −13 4 0.002 Disgust Fusiform gyrus (19) L −35 −53 −7 4 0.0005 Neutral a The cluster with the largest number of voxels within each region is reported. Talairach coordinates refer to the voxel with the maximum FPQ (fundamental power quotient) in each cluster. b All such voxels were identified by a one-tailed test of the null hypothesis that median FPQ is not determined by experimental design. The probability threshold for activation was PFull-size image (<1 K)0.004. c Signal increase was detected either during presentation of expressions of disgust or neutral baseline (mildly happy) expressions. Table options 3.2.8. Differences in neural response to facial expressions of disgust contrasted with neutral expressions in schizophrenics vs. normal controls Normal controls showed significantly greater activation compared with all 10 schizophrenic patients in response to expressions of disgust in the globus pallidus and insula (anterior). Activation in response to neutral expressions (deactivation in response to expressions of disgust) was demonstrated in the superior temporal gyrus (BA 22) (search volume=165 voxels; P=0.05; expected number of false positive activated voxels=8; observed number of activated voxels=32). No brain regions were activated significantly more in the 10 schizophrenic patients, as predicted. 3.2.9. Differences in neural response to facial expressions of disgust contrasted with neutral expressions in paranoid vs. non-paranoid schizophrenics Paranoid schizophrenics showed significantly greater activation compared with non-paranoid schizophrenics in response to expressions of disgust in the insula (anterior), and significant activation in response to neutral expressions (deactivation in response to expressions of disgust) in the superior temporal gyrus (BA 22), cerebellum and hippocampus. Non-paranoid schizophrenics showed significantly greater activation compared with paranoid schizophrenics in response to expressions of disgust in the superior temporal gyrus (BA 22), thalamus, postcentral gyrus (BA 43) and the amygdala (search volume=155 voxels; P=0.05; number of expected false activated voxels=7; observed number of activated voxels=66)