Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia

Abstract

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Fig. 1

Change detection task.

Fig. 2. MMN amplitude, BDNF genotypes and working memory.

Comparison of working memory capacity (A) and MMN amplitude (B) between the two genotype groups. C–F Correlations between working memory capacity and MMN amplitude across the genotype groups. Effects of BDNF genotypes on working memory capacity improvement in the prefrontal stimulation group (G), the parietal stimulation group (H) and the sham stimulation group (I). MMN, mismatch negativity; BDNF, brain-derived neurotrophic factor; K_T4, Cowan’s K under only four targets condition of the change detection task; K_T2, Cowan’s K under only two targets condition of the change detection task; T2_W1, only two targets condition of the change detection task at week 1; T2_W2, only two targets condition of the change detection task at week 2; T4_W1, only four targets condition of the change detection task at week 1; T4_W2, only four targets condition of the change detection task at week 2. *P < 0.05, ** P < 0.01, NS., not significant.