Association of enhanced limbic response to threat with decreased cortical facial recognition memory response in schizophrenia

Abstract

Objective: Recognition memory of faces is impaired in patients with schizophrenia, as is the neural processing of threat-related signals, but how these deficits interact to produce symptoms is unclear. The authors used an affective face recognition paradigm to examine possible interactions between cognitive and affective neural systems in schizophrenia.

Method: Blood-oxygen-level-dependent response was examined by means of functional magnetic resonance imaging (3 Tesla) in healthy comparison subjects (N=21) and in patients with schizophrenia (N=12) or schizoaffective disorder, depressed type (N=4), during a two-choice recognition task that used images of human faces. Each target face, previously displayed with a threatening or nonthreatening affect, was displayed with neutral affect. Responses to successful recognition and responses to the effect of previously threatening versus nonthreatening affect were evaluated, and correlations with symptom severity (total Brief Psychiatric Rating Scale score) were examined. Functional connectivity analyses examined the relationship between activation in the amygdala and cortical regions involved in recognition memory.

Results: Patients performed the task more slowly than healthy comparison subjects. Comparison subjects recruited the expected cortical regions to a greater degree than patients, and patients with more severe symptoms demonstrated proportionally less recruitment. Increased symptoms were also correlated with augmented amygdala and orbitofrontal cortex response to threatening faces. Comparison subjects exhibited a negative correlation between activity in the amygdala and cortical regions involved in cognition, while patients showed weakening of this relationship.

Conclusion: Increased symptoms were related to an enhanced threat response in limbic regions and a diminished recognition memory response in cortical regions, supporting a link between these two brain systems that are often examined in isolation. This finding suggests that abnormal processing of threat-related signals in the environment may exacerbate cognitive impairment in schizophrenia.

Figure 1. Experimental paradigm

A. Encoding task. Subjects initially performed an emotion identification task in which they identified the facial affect displayed. Four emotional labels were available, including two non-threatening affects (happy and sad), two threatening affects (angry and fearful), and neutral. Subjects were not instructed to remember the faces displayed. Emotion identification and face recognition experiments were separated by a 10-minute diffusion tensor imaging acquisition. B. Face recognition task. Following the affect identification task, subjects were asked to make a forced-choice facial recognition judgment. Thirty faces (targets) from the affect identification task and thirty novel faces (foils) were displayed for 2 seconds each. Subjects made a simple ‘old’ vs. ‘new’ judgment as to whether the face had been previously displayed in the affect identification task. Faces were separated by 60 variable (0–12s) intervals where a crosshair fixation point was displayed on a complex background (degraded face). Task duration was 4 minutes, 16 seconds.

Figure 2. HIT > CORRECT REJECTION contrast

A. Controls activate expected frontoparietal memory network, including lateral and medial parietal regions. B. Response of left inferior parietal lobule. As in other studies, the inferior parietal lobule responded robustly to HIT but not CORRECT REJECTION; MISS and FALSE ALARMS demonstrated an intermediate response. Error bars represent standard deviation. C. Controls demonstrate a greater response than patients in the posterior cingulate and the right middle frontal gyrus. D. Patients with more severe symptoms demonstrated a reduced HIT > CORRECT REJECTION response in both lateral and medial parietal regions.

Figure 3. THREAT > NON-THREAT contrast

A. Controls demonstrate a THREAT > NON-THREAT response in the left amygdala and right orbitofrontal cortex. B. In patients, severity of symptoms correlates with increased response to THREAT in right amygdala and right orbitofrontal cortex.

Figure 4. Functional connectivity analysis

A. Controls demonstrate a positive correlation with activity in a left amygdala seed in ventral limbic regions, and a negative correlation in cortical regions involved in cognition. B. The negative correlation between amygdala and left parietal clusters is related to performance in controls: subjects who performed less well demonstrated diminished anti-correlation. C. Patients show increased functional connectivity between the amygdala and other limbic regions as well as increased connectivity (reduced negative correlation) with cortical regions. D. Between-groups contrast. Compared to controls, patients show significantly reduced anti-correlation between the left amygdala and the right middle frontal gyrus and right inferior parietal lobule, as well as increased connectivity between the amygdala and the right orbitofrontal cortex, right insula, and midbrain.