Schizophrenia 3.0: Salience dysregulation.

This post is prompted by an article published in this February’s Trends in Neurosciences under the title “Dopaminergic Basis of Salience Dysregulation inPsychosis” by Winton-Brown, Fusar-Poli, Ungless, & Howes (2014) and an earlier paper in the Schizophrenia bulletin entitled “The dopamine hypothesisof schizophrenia: version II – the final common pathway” (Howes & Kapur, 2009). As stated in the first title, Winton-Brown et al.’s work reviews extensively what they consider to be evidence of the dopaminergic basis of salience dysregulation and more briefly consider the argument for salience dysregulation as a causal force in the etiology of schizophrenia. Their work was building on an argument made by Howes & Kapur who suggested that a panoply of genetic and environmental risk factors all converge on increased striatal dopaminergic function, producing aberrant salience and thereby psychosis.

Salience regulation can be understood as allocation of attentional resources only to the most relevant stimuli in an individual’s environment (e.g., a loud bang takes attention away from the computer screen, a moving light draws the eyes, etc.). Within this framework, schizophrenia patients appear to aberrantly attribute undue salience to what everyone else might see as irrelevant stimuli.

This dysregulation is thought to be mediated by abnormalities in dopaminergic neurotransmission in the striatum. Dopamine involvement in schizophrenia goes back to the beginnings of molecular neuroscience, specifically, to the discovery that antipsychotic agents act on dopamine receptors. Since then thousands of reports have been published investigating dopaminergic abnormalities in schizophrenia patients and in animal models of the disease.

Evidence abounds of aberrant dopamine action in schizophrenia and Winton-Brown’s et al.’s review makes a fairly persuasive argument for that being involved in salience dysregulation. In short, it appears that there are dopaminergic neurons in the substantia nigra pars compacta (and, possibly, the ventral tegmentum) which are activated in response to cues that have been associated with both positive and negative consequences. Activation of dopaminergic neurons in response to reward cues is no surprise, but finding neurons which react to stimuli with predicted consequences of either valence suggests that perhaps these neurons’ projections serve as more generic significance detectors. Along similar lines, animal studies are now showing that dopaminergic neurons respond to novel but innocuous visual and auditory stimuli (i.e., it is unlikely that it's all about reward). In human imaging studies, unmedicated first-episode schizophrenia patients show decreased responsiveness in the ventral striatum in response to reward cues. 

The sharpness of the response to attention-demanding stimuli may indeed be a good indication of salience. And, as is pointed out by Howes & Kapur, elevated dopamine release (presynaptically) in the striatum may result in abnormally strong salience of innocuous cues. From then on, however, this hypothesis leaves its stable biological underpinnings, positing that perhaps patients have the need to explain this strange sense of significance which they attribute to random features of the environment and they do so by creating elaborate stories. 

Many questions are left unanswered by this model, but it is very pleasing to see such theoretical bridges being formed between the neurobiological and psychological features of schizophrenia. As things stand, the salience dysregulation model of schizophrenia holds great promise.

References

Howes, O. D., & Kapur, S. (2009). The dopamine hypothesisof schizophrenia: version III--the final common pathway. Schizophrenia Bulletin, 35(3), 549–62. doi:10.1093/schbul/sbp006

Winton-Brown, T. T., Fusar-Poli, P., Ungless, M. a, & Howes, O. D. (2014). Dopaminergicbasis of salience dysregulation in psychosis. Trends in Neurosciences, 37(2), 85–94. doi:10.1016/j.tins.2013.11.003