Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

Abstract

Rationale: Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation.

Objectives: We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis.

Methods: An oral 1 mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3 T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory.

Results: Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task.

Conclusions: GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia.

Fig. 1

The experimental paradigm is illustrated above. Subjects initially performed an emotion identification task (a) in which they identified the facial affect displayed. Five emotional labels were available: happy, sad, anger, fear, and neutral. During the emotion memory task (b) that followed, subjects were asked to remember which expression had been previously displayed during the emotion identification task. One target emotion and two foils were displayed. In both tasks, faces were displayed for 5.5 seconds, followed by a variable (0.5–18.5s) interval during which subjects fixed their gaze on a complex crosshair that was matched to faces on perceptual qualities. Both tasks contained 60 trials in an event-related design; each task lasted 10.5 minutes, with a 2-minute delay between tasks

Fig. 2

Emotion identification imaging results: Family members of patients with schizophrenia displayed a significant reduction of amygdala activity during face identification when given alprazolam (ALP) relative to placebo (PLC). Controls did not demonstrate this effect. Error bars indicate standard error of the mean

Fig. 3

Emotion memory imaging results: Relative to placebo (PLC), alprazolam (ALP) produced a significant reduction of activity during emotional face memory in the amygdala and hippocampus in both controls and family members. Error bars indicate standard error of the mean