BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment

Abstract

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Conflict of interest statement

A.P.-L. serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Axilum Robotics, Constant Therapy, NovaVision, Cognito, Magstim, Nexstim and Neosync, and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging. The remaining authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1

Study design overview. Participants underwent an encoding visual memory task while receiving rTMS over the LFC (MNI coordinates: X = − 42; Y = 10; Z = 30, according to Martin-Trias and colleagues; pointed with a red arrow) or the vertex area (MNI coordinates: X = 4; Y = − 16; Z = 70, from Cz location according to Rojas et al., created for visual purposes, pointed with a yellow arrow). After a 30 min rest, participants completed the recognition of the visual memory task (i.e., discrimination between seen/not seen items in encoding phase) within the MRI scanner. RMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation; LFC, left frontal cortex; fMRI, functional magnetic resonance imaging.

Figure 2

TMS effects on cognition as a function of BDNF Val66Met gene polymorphism. Cognitive performance results considering (A) accuracy during encoding as well as (B) hits during recognition. Statistical analyses were performed via one-way repeated measures ANOVAs with experimental conditions as within-subject factor and BDNF Val66Met gene polymorphism as between-subject factor. Subsequent pair-wise analyses were conducted with t-tests. * Significant differences (p < 0.05). LFC, left frontal cortex.

Figure 3

TMS effects on brain activity as a function BDNF Val66Met gene polymorphism and its relationships with cognitive performance. (A,B) fMRI activity maps for the HF > HV contrast at both group differences (Val > Met) and mean Val group. (C,D) Scatter plots showing Pearson correlations between hits difference (i.e., LFC hits—vertex hits) and BOLD signal values within the ROIs displayed in (A,B), only considering the Val group. HF, hits frontal cortex; HV, hits cranial vertex; Diff, difference; LFC, left frontal cortex; BOLD, blood oxygen level dependent.