Underlying Mechanism of Auditory Impairment in Schizophrenia Reveals Potential Therapeutic Path

Benefits of NMDA receptor agonists in patients with schizophrenia include improvements with memory and reading.
Benefits of NMDA receptor agonists in patients with schizophrenia include improvements with memory and reading.

Dysfunction in N-methyl-D-aspartate (NMDA) brain receptors appears to contribute to the deficits in cortical plasticity that cause patients with schizophrenia to struggle with distinguishing slight changes in auditory pitch, suggests a new study.

The authors also propose that using NMDA receptor agonists may help improve those problems, which have correlated with problems in working memory and reading.

“We showed a robust across-group relationship between impaired auditory plasticity and impaired auditory emotion recognition, which is a critical component of social cognitive impairment in schizophrenia,” wrote Joshua T. Kantrowitz, MD, of Columbia University in New York City, and his colleagues in the study published in Brain.

People with schizophrenia who cannot distinguish between subtle variations in pitch struggle to recognize the emotional and social cues communicated by small changes in tone of voice, Dr Kantrowitz explained in a statement. This auditory deficit also contributes to difficulty in reading because detecting changes in pitch helps people sound out words while reading.

The findings reveal insights underlying the potential for auditory learning in people with schizophrenia.

“Schizophrenia is associated with deficits not only in ongoing cognitive performance, but also in ability to learn new information and improve performance with training (‘plasticity'), which limits the ability to benefit from rehabilitation approaches,” Dr Kantrowitz and his coauthors wrote. “While neural mechanisms underlying cognitive dysfunction have been extensively studied, neural mechanisms underlying plasticity deficits have been evaluated to a much lesser degree.”

The researchers assessed cortical plasticity in 40 patients with schizophrenia or another schizoaffective disorder and in 40 control patients with no mental health diagnosis. The participants had to identify which tone from a pair was higher. Correctly identifying it led to another pair whose tones were closer together. If participants got it wrong, the next pair of tones was adjusted to be easier to distinguish.

The control participants got gradually better at discerning the difference between the tones, learning through listening as is expected from those with normal auditory plasticity. They were eventually able to distinguish between tones that were just 3% different. But those with schizophrenia could only distinguish between tones that differed by 16% and showed lower brainwave activity on EEG during the exercise. The patients with schizophrenia had significantly reduced auditory plasticity overall, which paralleled cognitive, occupational, and social dysfunction. 

To test the involvement of NMDA in this deficit, the researchers conducted a separate test with 21 different patients with schizophrenia or another schizoaffective disorder and 13 different healthy controls. The participants received either a placebo or D-serine, an amino acid that activates NMDA receptors, once a week for 3 weeks.

Patients with schizophrenia improved their ability to detect pitch differences when they took the D-serine for at least 2 weeks while undergoing the auditory training exercises. Those taking placebo or taking D-serine for only 1 week, however, showed no improvement.


Kantrowitz JT, Epstein ML, Beggel O, et al. Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D serine. Brain. 2016;139:3281-3295. doi: 10.1093/brain/aww262 

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