Altered neural oscillations are associated with improved working memory performance in schizophrenia following D-cycloserine administration

Abstract

Cognitive deficits, such as impaired working memory, are a core feature of schizophrenia and a key target for intervention that have been hypothesized to reflect hypofunction at the N-methyl-d-aspartate glutamate receptor (NMDAR). Working memory depends on neural oscillations in the gamma (30–80 Hz), theta (4–7 Hz), and alpha (8–13 Hz) frequency bands, with gamma oscillations known to be strongly impacted in schizophrenia and to be sensitive to NMDAR hypofunction. Importantly, in a previous double-blind randomized placebo-controlled study, findings suggested that n-back working memory performance was improved in schizophrenia patients who received 100 mg of the NMDAR agonist D-cycloserine (SZ-DCS; n = 17) compared to patients who received placebo (SZ-placebo; n = 16; Forsyth et al., 2017). To understand potential mechanisms underlying this effect, the current study examined electroencephalogram data collected during this study to identify whether gamma, theta, and alpha oscillations were altered in patients who received DCS versus placebo. Results revealed reduced working memory-related gamma power in right frontal and occipital channels from 1 to 1.5 s post-stimulus onset in SZ-DCS versus SZ-placebo patients. SZ-DCS patients also showed reduced frontal theta power relative to SZ-placebo patients across memory loads. Conversely, SZ-DCS patients showed increased left-hemisphere alpha power during the 0-back control condition, without differences during working memory loads. Our findings suggest that increasing NMDAR signaling in schizophrenia may improve working memory performance by increasing the efficiency of gamma and theta oscillations that support working memory demands, as well as enhancing alpha oscillations that support preparatory attentional processes.