Schizophrenia Research Forum - A Catalyst for Creative Thinking

Deconstructing Negative Symptoms in Schizophrenia

19 October 2012. Even when medication succeeds in tempering their psychosis, most people with schizophrenia struggle to create full, meaningful lives with independent living, jobs or education, and satisfying personal relationships. How well they do this may have some roots in visual perception, according to a new modeling study published online 1 October in Archives of General Psychiatry. Led by Michael Green of University of California, Los Angeles, the study mathematically explores how the disparate features of the disorder fit together by drawing on comprehensive assessments of 191 people with schizophrenia. A linear pathway fit the data best, with visual perception performance linked to social cognitive abilities, which were then associated with motivation and beliefs about self, which then correlated with functional outcome. This kind of chain reaction suggests that treatments targeting perceptual abnormalities could ultimately improve a person’s everyday functioning.

“It’s a very nice story,” said SRF advisor James Gold of University of Maryland, Baltimore, who was not involved in the study. “I’m impressed at how you can take a table of intercorrelations like the one that they’ve published and turn it into this elegant model.”

Though previous studies have linked perceptual abnormalities to deficits in cognition, specifically social cognition (see SRF related news story), the new study extends their reach to negative symptoms and functional outcome. Negative symptoms, which include a profound loss of motivation and goal-directed behavior, have the strongest influence on functional outcome, yet clinicians are at a loss for how to treat them, as they go mostly untouched by antipsychotic medication. The new study, and one published in February in Archives of General Psychiatry by Gold and colleagues, attempts to deconstruct negative symptoms into their component parts, which may make their treatment more tractable (Keefe and Kraus, 2012). Gold’s study suggests that negative symptoms stem from faulty reinforcement learning, and the specific impairments implicate cortical inputs to the striatum.

Perception pathway
The new study from Green and colleagues formally explores an intuitive idea that decreased cognitive abilities may give rise to the negative thinking and lack of motivation that undermine everyday functioning for people with schizophrenia (Beck et al., 2005). Though their previous research linked perception to social cognition, and thence to functional outcome (Sergi et al., 2006), the new study asks where negative symptoms fit into this. Do cognitive abilities and motivation/self-defeating beliefs act independently on functional outcome, or are they part of a single pathway?

First author Green and colleagues collected mounds of data from 191 clinically stable people with schizophrenia in four different domains: visual perception, ability (measures of social cognition involving emotion processing, theory of mind, and interpretation of nonverbal social cues), motivation/beliefs (assessments of negative symptoms and dysfunctional attitudes), and functional outcome (measures related to work, independent living, family and social function). Using structural equation modeling, a statistical technique for measuring how well one set of data correlates with another, the researchers found that the functional outcome data could be accounted for by a single pathway that began with visual perception, continued with social cognition, followed by beliefs/motivation; this model explained 49 percent of variance in functional outcome scores. Notably, the model was not improved by playing with the placement of the beliefs/motivation domain, either by separating it into its own pathway impinging upon functional outcome, or by eliminating it altogether. While this approach by no mean proves this is how it all works, it adds supportive evidence and suggests that perturbations in sensory processing can cascade into fairly complex deficits in motivation and function.

Representing value
Gold’s study earlier this year in the Archives explores whether negative symptoms may develop from impairments in the processes of reinforcement learning. In reinforcement learning, rewards teach that a certain action produces a desirable outcome, whereas a lack of a reward, or even punishment, signals something less desirable. Throughout the day, we are constantly learning associations between our actions and outcomes, and storing them away for the future. When something unexpected happens that does not fit with these stored associations, dopamine signals are thought to flag the “prediction error” and reshape the association so that it more accurately reflects reality. Problems with this process, either in encoding associations or attaching a relative value to them, might lead to an unmotivated person who exhibits little goal-directed behavior —when faced with a decision about what to do, it’s all the same to them.

Gold and colleagues dissected the reinforcement learning process in 47 people with schizophrenia and 28 healthy controls. In the first phase, two kinds of stimulus pairs were presented: for one pair, selecting one stimulus garnered a monetary reward, and selecting the other resulted in no loss of money; for the second pair, selecting one stimulus resulted in money loss, and selecting the other no loss (“loss-avoidance”). In the second phase, these stimuli were paired across categories (e.g., a loss avoidance stimulus could be paired with a reward stimulus), and participants had to choose the “best” one, thus indicating its value relative to the other stimulus.

In the first phase, people with high negative symptoms (n=25) were impaired in learning from rewards, selecting the reward stimulus less frequently than controls or people with low negative symptoms (n=22). Their learning from loss-avoidance, however, was intact, suggesting that they were driven more to preserve what they had rather than to gain something more. Though loss avoidance and reward are both positive outcomes, reward is one step better. But this distinction seemed lost on the high negative symptom group, which did not show the bias for reward stimuli observed in the control and low negative symptom groups. This suggests that those with high negative symptoms have trouble with representing the value of a predicted outcome —something prefrontal cortical circuitry is responsible for. This could blur the differences between choices encountered by a person, and lead them to an unmotivated, apathetic state.

This scenario differs from the abnormal dopamine signaling in reinforcement learning that has been proposed to underlie positive symptoms (“aberrant salience”) ( Kapur, 2003). But it suggests a complex architecture behind cognition that might be altered in different ways to produce both positive and negative symptoms in schizophrenia.

In similar vein, in a review article published in April, Gregory Strauss of Maryland and Gold explore the mechanisms behind the lack of pleasure, or anhedonia, that forms part of negative symptomology (Strauss and Gold, 2012). There they suggest that what is clinically rated as anhedonia actually reflects memory abnormalities that influence how pleasure is recalled or anticipated, rather than an inability to experience pleasure.

“For a long time people had almost nothing to say about negative symptoms, other than that they were really bad,” Gold told SRF. “Now these three papers address the role of perceptual, working memory, and episodic memory representations, and how those alter motivation, or alter the experience of emotion, and perhaps undermine volition. So on some level we’re all barking up similar trees.”—Michele Solis.

References:
Green MF, Hellemann G, Horan WP, Lee J, Wynn JK. From Perception to Functional Outcome in Schizophrenia: Modeling the Role of Ability and Motivation. Arch Gen Psychiatry. 2012 Oct 1:1-9. Abstract

Gold JM, Waltz JA, Matveeva TM, Kasanova Z, Strauss GP, Herbener ES, Collins AG, Frank MJ. Negative symptoms and the failure to represent the expected reward value of actions: behavioral and computational modeling evidence. Arch Gen Psychiatry. 2012 Feb;69(2):129-38. Abstract

Comments on News and Primary Papers
Comment by:  Laurie Kimmel
Submitted 25 October 2012
Posted 26 October 2012

As a clinician, I find this research encouraging.

View all comments by Laurie Kimmel

Comments on Related News


Related News: SfN 2013—Different Roads to Dopamine Dysfunction in Schizophrenia

Comment by:  Melkaye Melka
Submitted 5 December 2013
Posted 9 December 2013

Atypical antipsychotics have been used to treat psychiatric disorders such as schizophrenia. However, the mechanisms of action of antipsychotics remain poorly understood. On the other hand, dopamine neurons form the focus of attention in the etiology and pathophysiology of schizophrenia. As noted by Michele Solis’ snapshot from the conference, the work of Grace and colleagues showed that prenatal injections of methylazoxymethanol acetate (MAM), a DNA-methylating agent, lead to hyperactive dopamine signaling (Moore et al., 2006). Focusing on the mechanisms of action, previous studies have suggested that antipsychotic drugs may cause promoter methylation of genes involved in psychosis (Dong et al., 2009). DNA methylation changes have also been associated with major psychosis (Mill et al., 2008).

In a recent in-vivo study, we have observed organ-specific (hippocampus, cerebellum, and liver) changes in DNA methylation following a therapeutic dose of a model antipsychotic drug (olanzapine) (Melka et al., 2013, in press). In particular, we noted that the dopamine signaling pathway was one of the most significant networks affected by olanzapine-induced DNA methylation changes. Specifically, the results showed that olanzapine significantly alters promoter DNA methylation of genes involved in dopamine synthesis, transport, receptors, and metabolism. These results support a dopamine hypothesis of psychosis and a role for epigenetic mechanisms in the development of psychosis, as well as its treatment with antipsychotic drugs. Given that some of the genes affected are tissue specific and affect a variety of networks, our results could also explain the delayed therapeutic response of antipsychotics as well as their patient-specific efficacy and side effects.

References:

Dong E, Grayson DR, Guidotti A, Costa E. Antipsychotic subtypes can be characterized by differences in their ability to modify GABAergic promoter methylation: Epigenomics 2009; 1: 201-1. Abstract

Melka MG, Castellani CA, Laufer BI, Rajakumar N, O’Reilly R and Singh SM. Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis. J Mol Psychiatry; 2013; 1:19. (In press)

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet . 2008 Mar ; 82(3):696-711. Abstract

Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry . 2006 Aug 1 ; 60(3):253-64. Abstract

View all comments by Melkaye Melka