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Beyond Cortex—Amygdala and Midbrain Dysfunction in Schizophrenia

8 January 2011. Two functional brain imaging studies of people with schizophrenia find abnormal activity in the amygdala, the brain region known for processing emotionally salient stimuli. In one study, anomalous activity was also found in the midbrain, which contains dopamine neurons that modulate activity throughout the brain. Inappropriate activity in these and related regions could impair emotion perception or underlie delusions, and may be fertile ground for schizophrenia research, which has been dominated by studies of prefrontal cortex and striatum.

One of the studies, led by Amy Pinkham while at Ruben and Raquel Gur's group at the University of Pennsylvania, Philadelphia, reports that activity in the amygdala is modulated differently in schizophrenia when study subjects view emotional facial expressions, depending on direction of eye gaze. Published online December 15 in the American Journal of Psychiatry, the study also found that in the schizophrenia group, some amygdala activity correlated with a measure of social and occupational functioning. The second study, led by Jeremy Hall at the University of Edinburgh, Scotland, appeared in the December issue of Archives of General Psychiatry. The researchers tracked activity in the amygdala and other regions during a classical conditioning paradigm. Not only did they find abnormal activation of the amygdala, midbrain, and ventral striatum, but the midbrain activity correlated with severity of delusions in the schizophrenia group. Together, the studies suggest that studying how emotional meaning is attributed to different kinds of stimuli could be a fruitful approach for understanding aspects of schizophrenia.

The eye gaze has it
Pinkham, who now has her own lab at Southern Methodist University in Dallas, Texas, and colleagues used functional MRI to measure neural activity in 35 participants with schizophrenia and 37 controls as they viewed faces with angry, fearful, or neutral expressions. Though previous studies had shown that the direction of gaze—either direct or averted—could modulate amygdala responses in schizophrenia (Kohler et al., 2008), this study was the first to manipulate both gaze and emotion.

Controls were better at accurately recognizing the emotion—fear or anger—in the facial expressions, getting it right for 83 percent of the faces compared to 74 percent by the schizophrenia group. For subjects with schizophrenia, the amygdala response while viewing these faces relative to a scrambled baseline face was significantly reduced compared to controls. Their responses to three other conditions—averted-gaze anger, direct-gaze fear, and averted-gaze fear—were within normal range, which contrasts with previous suggestions that the amygdala is generally underactive in schizophrenia (Li et al., 2010).

Within the schizophrenia group, amygdala activity in response to direct-gaze anger correlated with two different clinical measures: anhedonia and the Strauss-Carpenter outcome scale score, which measures social and occupational functioning. These amygdala responses were negatively correlated with anhedonia, with lower activations related to high ratings of anhedonia (r = -0.564, p <0.001), and positively correlated with the outcome score, with lower activations related to lower social and occupational functioning (r = 0.587, p <0.001).

Abnormal brain activation during learning
At the University of Edinburgh, first author Liana Romaniuk and colleagues measured activation in the amygdala and other brain regions in 20 participants with schizophrenia and 20 controls using an aversive conditioning task. This involved learning to associate a particular color with either an aversive image (e.g., a gun) or a neutral one (e.g., a wicker basket).

Though both control and patient groups learned to associate the appearance of a color with an aversive picture, their brain activity differed. While controls acquired a conditioned response in the amygdala to presentation of the color predicting an aversive image, the schizophrenia group did not. Further examination revealed abnormal activation of the midbrain and ventral striatum during conditioning in the schizophrenia group, and the midbrain responses correlated to delusional symptoms, as rated by the Positive and Negative Syndrome Scale (PANSS). This correlation stemmed largely from inappropriate midbrain responses to neutral conditioned stimuli in individuals with higher delusion scores, and remained significant after controlling for medication dosage. These findings support the idea that problems with assigning importance to stimuli appropriately may lead to delusional beliefs (Kapur, 2003).

Because the relationships between brain activation and clinical measures found in both studies are correlations, it is unclear whether these activations cause or reflect these symptoms. But the link emphasizes the relevance to schizophrenia, and argues that research could delve more deeply into the somewhat messy, "emotional" terrain of these subcortical brain systems.—Michele Solis.

Pinkham AE, Loughead J, Ruparel K, Overton E, Gur RE, Gur RC. Abnormal Modulation of Amygdala Activity in Schizophrenia in Response to Direct- and Averted-Gaze Threat-Related Facial Expressions. Am J Psychiatry. 2010 Dec 15. Abstract

Romaniuk L, Honey GD, King JR, Whalley HC, McIntosh AM, Levita L, Hughes M, Johnstone EC, Day M, Lawrie SM, Hall J. Midbrain activation during Pavlovian conditioning and delusional symptoms in schizophrenia. Arch Gen Psychiatry. 2010 Dec; 67:1246-54. Abstract

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