27 Dec 2016
by Lesley McCollum
A study published December 7 in JAMA Psychiatry suggests that abnormal processing of auditory information, commonly observed in patients with schizophrenia, initiates a cascade of poor cognition leading to impaired daily functioning. Gregory Light of the University of California, San Diego, and colleagues used computational modeling to look for patterns of association among auditory information processing, cognition, clinical symptoms, and functional assessments of 1,415 people with schizophrenia. Pathways defined by the model indicate how deficits in sensory processing mightresult ultimately in things people care most about, such as problems at work, school, and in relationships.
Although everyday functional impairments are closely tied to cognition, cognitive functioning remains largely unresponsive to available treatments. “Understanding how deficits arise at their most basic level might one day inform precision medicine and tailored intervention,” said first author Michael Thomas, also of the University of California, San Diego.
Previous modeling efforts have been made to characterize pathways linking deficits in early auditory information processing (EAP) and functional outcome (see SRF related news story). The new study further clarifies the relationships by making use of the wealth of diverse laboratory and clinical data from the Consortium on the Genetics of Schizophrenia (COGS)-2.
“The study is impressive both from the point of view of sample size and technical expertise,” said Daniel Javitt of the Nathan S. Kline Institute for Psychiatric Research and Columbia University in New York, who was not involved in the study.
Three measures of EAP—mismatch negativity (MMN), P3a, and reorienting negativity—were derived from signature components of electroencephalography (EEG) recordings of brain activity collected while patients listened to sounds. Though widely used as research tools, measures such as MMN have yet to demonstrate utility in the clinic as potential biomarkers.
“This study goes a long way to demonstrating that MMN (and potentially other neurophysiological biomarkers) could one day be incorporated into routine clinical practice and could be used for purposes such as clinical diagnosis and treatment selection,” said Javitt.
“Early auditory information processing is certainly a lot easier to assess than higher-level cognition,” said Judith Ford of the University of California, San Francisco, who was not involved in the study. She agrees that EAP intervention is a promising strategy and feasible for use in a clinic.
Thomas and colleagues used structural equation modeling to fit a series of models to the data, each testing the plausibility of different causal hypotheses and the direction of interactions. To determine if the negative symptoms would differentially affect functional outcome, the researchers divided negative symptoms into expressive (such as blunted emotion and loss of speech) and experiential (such as reduced motivation and enjoyment). Assessments of functional outcome included working productivity, independent living and self-care, and social network relationships.
The analysis revealed that a bottom-up deficit model best explained the data. Some patients show deficits in basic functional brain processes, said Thomas, that appear to multiply and cascade forward as you move closer to cognition and psychological traits that are more directly related to outcomes such as performance at work and school.
According to Javitt, the model provides independent support for the hypothesis that dysfunction in the earliest stages of processing is most important. Of the three measures used to assess EAP, MMN occurs the earliest, is least affected by attention, and had the largest effect on the EAP construct. He noted that an emerging theme in schizophrenia research is that deficits may start in lower levels of the brain and involve specific pathways with higher-level brain regions. “The earlier and more automatic the processes are that break down, the harder it is for individuals to compensate for them using alternative networks,” he said.
Auditory and visual cognitive tasks were assessed, with the assumption that impairments in EAP would be more strongly associated with auditory tasks. But the researchers instead found that EAP associated with both auditory and visual cognitive domains.
“[The] results support the view that abnormal measures of EAP in schizophrenia reflect impaired brain functioning rather than a specific and unique deficit in auditory information processing,” wrote Sophia Vinogradov of the University of Minnesota, and Srikantan Nagarajan of the University of California, San Francisco, in a commentary accompanying the paper.
Experiential negative symptoms and functional outcome emerged as the strongest relationship in the model. The logic makes sense—if you have trouble leaving the house, it’s probably going to be pretty detrimental for your work and social relationships.
"I think that the negative symptoms like avolition and apathy, which the authors call ‘experiential negative symptoms,' are really at the heart of why people with schizophrenia have poor functional outcomes," said Ford.
“The provocative finding of the present study is that experiential negative symptoms do not arise de novo, but are driven in part through early auditory deficits via cognition,” said Javitt, adding that this implies that remediation of early auditory deficits might lead to significant improvements not only in cognition, but also in features of schizophrenia such as apathy or asociality.
The model also showed a direct effect of cognition on poor functional outcome, bypassing negative symptoms. “That was counter to the hypothesis,” said Thomas, noting that they expected functional outcome to be fully mediated by a single pathway through negative symptoms.
The finding indicates that patients with schizophrenia struggle with work and school not just because of a lack of motivation or interest in social relationships, but because basic laboratory-assessed measures of cognition such as attention, problem-solving, and memory have real-world significance for these outcomes as well.
According to Javitt, the direct association agrees with common sense. “Individuals who perform tasks more quickly and successfully will work more productively,” he said. However, he added that the use of eight tasks to represent “cognition” in the study makes it hard to test whether there are specific pathways that mediate the contributions of sensory processing deficits to impaired outcome.
A future step will be getting the neuroscience tools out of the lab and into the clinic, says Thomas. It’s harder to translate how a specific lower-level brain deficit, such as that in EAP, matters for daily life than it is with problems in attention or memory. But EAP measures are based on EEG, which is objective, cheap, and provides specific measures of brain function that could be targeted.
The model implies that “treatment that vigorously addresses EAP abnormalities in schizophrenia may have beneficial and generalizable benefits on cognition and functioning,” wrote Vinogradov and Nagarajan.
The idea is already backed with support from studies showing that measures of auditory information processing can be altered (Swerdlow et al., 2016), and that targeting auditory information processing can improve measures of higher-order cognition (see SRF related news story). The pathways clarified by the model outline a strategy for targeting EAP as an intervention and for using it as a biomarker to identify who would be a good candidate for the treatment.
“Improving early auditory information processing might plant the seeds for better cognition,” said Thomas, “and over time, we would expect that to result in better functional outcome.”