Emotions in Unmedicated Patients With Schizophrenia During Evaluation With Positron Emission Tomography

Eighteen patients suffering from DSM-IV schizophrenia were studied. Diagnoses were based on a structured interview, the Comprehensive Assessment of Symptoms and History (20). The patients with schizophrenia were all medication free for at least 3 weeks, a period after which oral neuroleptics are no longer measurably present in the brain (21). None had received depot neuroleptics in the past 6 months. Six patients were drug naive, and 12 had discontinued medications themselves, had them discontinued by a referring physician, or had them withdrawn while on the inpatient unit of the Iowa Mental Health Clinical Research Center after giving written informed consent and being fully informed about the risk of relapse. Three had comorbid substance abuse (one with amphetamine dependence, one with cannabis abuse, and one with amphetamine abuse and cannabis dependence); there were no other comorbid diagnoses. Sixteen patients were men, and two were women. Their average age was 30.0 years (SD=8.9), and their mean education level was 12.9 years (SD=3.3). Thirteen were right-handed, two were left-handed, and three used both hands. Symptom ratings obtained on the day of scanning indicated that symptom levels were in the mild to moderate range, a level that did not interfere with their ability to perform the tasks. Symptom dimensions (22, 23) were negative (mean=2.53, SD=1.19), positive (psychotic) (mean=2.53, SD=1.19), and disorganized (mean=2.55, SD=1.43). Two subjects experienced auditory hallucinations during all three imaging sessions, as determined by debriefing after each scan acquisition.

Seventeen healthy volunteers, recruited from the community by newspaper advertising, were studied. They were screened with an abbreviated version of the Comprehensive Assessment of Symptoms and History to rule out psychiatric, neurological, and general medical illness, including substance abuse. Nine were women, and seven were men. All were right-handed. Their average age was 29.5 years (SD=7.56), and their average educational achievement was 14.3 years (SD=1.7). All subjects gave written informed consent for this protocol, as approved by the University of Iowa Human Subjects Institutional Review Board. Findings regarding these 17 healthy volunteers were reported elsewhere (19).

The emotion attribution protocol used in this study was fully described elsewhere (19). In brief, two sets of stimuli (comprising 18 pleasant and 18 unpleasant pictures) were selected from the International Affective Picture System (24) to achieve a wide range of emotional content for each type of valence. Pleasant content depicted such emotions as success, beauty, or appetite, whereas unpleasant content included emotions such as fear, disgust, or disappointment. The pictures were screened before a large number of normal local volunteers who were of an age equivalent to those in this study and rated for valence. The pictures with the smallest standard deviations were selected and presented again to a similar large group of volunteers. Based on their ratings, 18 pictures were selected for each condition, chosen to achieve pleasant or unpleasant valence, and matched for types of content (e.g., people, objects, scenes). A complete list of pictures can be found in a previous study (19). Mean image luminance was 12.37 foot-candles (SD=0.49) for the set of unpleasant pictures and 12.47 (SD=0.49) for the pleasant set. Before presentation of the pictures and the imaging, the subjects were familiarized with the use of the visual analogue scale. Before the imaging, they were instructed as follows:

Picture displays began 10 seconds before the arrival of the bolus in the brain. After the images were acquired, the subjects looked at a –7 (extremely unpleasant)-to-0 (neutral)-to-7 (extremely pleasant) visual analogue scale that was held by a research technician and made their ratings by pointing to a specific number. The order of presentation was “pleasant” followed by “unpleasant” to minimize possible carryover effects of intensity (25). Mean normative arousal scores (range=0–9) were 5.73 (SD=0.74) for the unpleasant set and 4.69 (SD=1.03) for the pleasant set. These two conditions were part of a larger PET study that also included exposure to odors. The results of the olfaction study have been reported elsewhere (26).

rCBF was measured by using the bolus [¹⁵O]H₂O method (27). The subjects were oriented in the PET scanner with laser light guides aligned at the orbital meatal line of the brain. The center of the most rostral slice was indicated by the laser guides. Fifteen slices (6.5 mm, center to center), with an intrinsic in-plane resolution of 6.5 mm full width at half maximum and a 10-cm axial field of view, were acquired. The images were reconstructed by using a Butterworth filter (cutoff frequency=0.35 Nyquist). CBF was determined by using [¹⁵O]H₂O (a 50 mCi/injection) and methods described previously (28). For each injection, arterial blood was sampled from time=0 (injection) to time=100 seconds. The imaging was initiated at the time of injection and consisted of 20 frames at 5 seconds per frame for a total of 100 seconds. The parametric (i.e., CBF) image was created by using a 40-second summed image (initial=40 seconds immediately after the bolus transit) and an arterial input function. A preliminary (“sham”) injection, to determine the bolus arrival time, was employed to establish stimulus timing (29). An 18-mm Hanning filter was applied to the PET images to eliminate residual anatomical variability. Magnetic resonance imaging (MRI) consisted of contiguous coronal slices (1.5-mm thick) acquired on a 1.5-T GE Signa scanner (General Electric Systems, Milwaukee). The technical parameters of the MRI acquisition were as follows: spoiled gradient recall acquisition sequence, flip angle=40°, TE=5 msec, TR=24 msec, number of excitations=2. MRI was analyzed with locally developed software (BRAINS, University of Iowa, Iowa City). All brains were realigned parallel to the anterior commissure-posterior commissure line and the interhemispheric fissure to ensure comparability of head position across subjects. Alignment also placed the images in standard Talairach space (30). Images from multiple subjects were coregistered and resliced in three orthogonal planes to produce a three-dimensional data set that was used for visualization and analysis (31).

The data presented here are based on a nonparametric randomization analysis, with use of the statistical methods described previously (32). The analysis shown compares the response of patients and comparison subjects on the two most extreme emotion-attribution tasks: very pleasant versus very unpleasant pictures. This comparison was powerful for comparing patients and comparison subjects because it examined the extremes of emotional response. Randomization analysis relies on across-task and across-group comparisons for unpleasant minus pleasant pictures in patients as opposed to unpleasant minus pleasant pictures in comparison subjects. We used an uncorrected alpha of 0.005.

The patients with schizophrenia were unable to engage neural nodes known to be responsible for processing negatively charged affective stimuli, including the amygdala, the hippocampus, and the ventral medial frontal cortex. Functional imaging studies have reported amygdala abnormalities in patients with schizophrenia who responded with the appropriate affect to sadness-inducing human faces (42) and in patients who failed to respond to fearful faces (43). Hence, our study is consistent with previous reports of functional abnormality in the amygdala of patients during probes by negative stimuli. In the present study, the findings concerning the amygdala were left lateralized. This phenomenon may be due to the nature of our stimuli. The human amygdala may respond with right-lateralized activity to affect-laden human faces and with left-lateralized activity to nonhuman scenes (44) or in circumstances requiring a cognitive representation of fear (45). Our study helps clarify that the processing of faces is likely not the only causative factor for abnormal amygdala function (46). Adding to the mapping of amygdala dysfunction is another difference between studies. In the study by Schneider et al. (42), subjects were asked to rate their subjective mood rather than attribute a valence to stimuli, unlike the study by Phillips et al. (43) and ours. In agreement with previous studies (10), in our study, failure to engage the amygdala was consistent with the appropriate attribution of valence. It is worth noting, however, that at least two studies did not show reduced amygdala response to affective stimuli (9, 11). These findings may be explained on the basis of active neuroleptic medication in patients during task performance.

Animal and human studies have demonstrated that the amygdala plays a key role in the affective evaluation of negative or dangerous situations (17, 19, 47–53). It has been called “the hub in the wheel of fear,” since it acts as a router that permits a rapid and adaptive response to dangerous stimuli and a slower, more reflective response after the meaning of the stimulus has been assessed (17). The slow response is mediated by the hippocampus, which responds to unexpected stimuli as part of a novelty-assessment network by retrieving stored contextual and emotional experiences that permit attribution of meaning or valence to the stimuli (54, 55). The ventral frontal cortex is also part of this emotion appraisal network (18, 56, 57). Other regions showing decreased activity in schizophrenia include the visual association cortices, which also participate in determination of meaning through recognizing the specific nature of perceptions, such as in faces or objects (48).

Abnormalities in the thalamus are consistent with a growing number of postmortem, in vivo morphometric, and functional imaging studies that describe primary abnormalities in the thalamus in schizophrenia (58–64). Functional imaging studies have also shown that the thalamus is associated with visually induced negative affect (65, 66).

An abnormality in midline cerebellar activity in patients during an emotional valence recognition task is consistent with the posited role of the cerebellum in emotion (67, 68). Cerebellar midline structures (i.e., the vermis), together with other older cerebellar regions (i.e., the fastigial nuclei and the floccular nodular lobule) have been regarded as the equivalent of the limbic cerebellum (69) and have been found to be abnormal in schizophrenia (70). A large decrease in CBF was also observed, however, in the cerebellar cortex. Failure to recruit the cerebellum, along with other nodes in the cortical-cerebellar-thalamic-cortical circuit, completes an impairment posited to be the central unifying mechanism of symptom production and cognitive disturbance in schizophrenia (71). Therefore, the present study extends to emotion processing the findings of previous imaging studies obtained by using cognitive paradigms that did not include emotion (72).

This study did not find areas of relative increase in CBF in patients with schizophrenia relative to comparison subjects in either task. This paucity of activation (the “silent brain”) is consistent with our within-group analysis showing little differential activation in patients responding to unpleasant versus pleasant stimuli. However, consistent with the data of Taylor et al. (9), small areas of increased CBF were found in the ventral prefrontal cortex in association with correct interpretation of unpleasant stimuli and in response to pleasant stimuli in the within-group analyses of the patients.

Although the normal comparison subjects activated an archaic danger-recognition system when rating the unpleasant pictures, they activated multiple sites in the phylogenetically younger network of pleasure-recognition sites in the prefrontal cortex and in the insular cortex when rating the pleasant pictures (19). In contrast, as shown in Table 1 and Figure 2, the patients with schizophrenia had pervasive decreases in CBF in multiple regions of the prefrontal cortex while attempting to attribute the correct emotional valence to pleasant stimuli. These results are consistent with numerous studies that have previously demonstrated both structural and functional abnormalities in the prefrontal cortex in schizophrenia (73–84).

The patients also had decreased CBF in the insular cortex while attempting to attribute the correct emotional valence to pleasant stimuli. Decreased CBF in the insula in patients with schizophrenia is consistent with previous studies that have shown functional and structural abnormalities in the insular cortex in schizophrenia (85–87). The insular cortex is a multimodal integration region that is involved in the linking of sensory experiences with their appropriate emotional responses (88, 89). Previous functional neuroimaging studies have reported abnormalities in CBF in the insula during diverse emotional states, including the experiencing of aversive stimuli, nociception, anticipatory anxiety, and mood provocation (89–92). Insular gray matter volume and cortical surface size are inversely related to the severity of psychotic symptoms in schizophrenia (93).

These results indicate that patients with schizophrenia have at least two facets of neurofunctional deficits. The first one, which might be called condition independent, has been observed in patients, regardless of the mental task at hand, and entails deficits in frontal-thalamic-cerebellar circuitry. The results of this study are similar to those obtained in others in which patients performed “pure” cognitive tasks (94, 95). On the other hand, condition-specific deficits were also observed during this study of emotion. These were seen in regions governing affect regulation. Condition- or task-specific neurofunctional deficits are often found together with task-independent deficits in functional neuroimaging studies of schizophrenia (26, 96).

The results observed at the neural level, by means of measurements of CBF, are consistent with the clinical picture of schizophrenia, especially when examined in the context of the ratings of emotional valence given by the patients. The blunting of subjective experience and emotional expression are common symptoms in schizophrenia and are clinically referred to as part of the group of negative symptoms (anhedonia, asociality, and affective blunting). The patients in this study had difficulty in attributing the correct valence to pleasant pictures. They lacked the “normal” ability to recognize pleasant stimuli. However, they were able to attribute correctly an unpleasant or negative valence to the unpleasant pictures. Maintaining an intact behavioral response to aversive stimuli conveys survival advantages for people with schizophrenia, but their inability to recognize and attribute a positive valence for pleasant pictures is reflective of the suffering that they experience during survival.

Examination of the correlations between symptom patterns and the ability to attribute the correct emotional valence to the stimuli added to the clinical perspectives of this study. The patients who had higher levels of positive symptoms (delusions and hallucinations) were more likely to give the unpleasant pictures a more negative rating, seeing them as extremely unpleasant. This suggests that these patients had an unusual sensitivity to negative stimuli, making them more vulnerable to misinterpretation of their emotional meaning. This unusual sensitivity may form part of the basis for misperceptions and delusional interpretations. On the other hand, the patients who had higher scores on the negative dimension (i.e., anhedonia, affective blunting, asociality) also had difficulty in giving the correct (negative) rating to the unpleasant pictures, instead giving them a relatively more positive rating. This correlation between severity of negative symptoms and an inability to recognize the negative emotional valence of unpleasant pictures may explain other facets of the clinical experience of schizophrenia. Specifically, this rating pattern is consistent with clinical manifestations, such as both the blunting of affect and inappropriate affect.

In summary, we found that when patients evaluated the unpleasant pictures, they did not engage the limbic and paralimbic regions used by the healthy volunteers, even though they correctly rated them as unpleasant. The patients also failed to activate the areas of the prefrontal cortex that are normally used to recognize images as pleasant, but in addition, they were unable to recognize them as pleasant. This network of decreases in CBF during attribution of a positive or negative valence to pleasant or unpleasant visual stimuli in patients with schizophrenia suggests a failure in the functional brain systems used for recognition of the emotional significance of people, situations, and objects.