Sex modulates the effect of HD-tDCS over the prefrontal cortex on the Iowa Gambling Task

Decision-making under uncertainty (risky and ambiguous) is important for everyday life (Knight, 1921). The Iowa Gambling Task [] is a widely-used tool to measure decision making under uncertainty [,]. Previous research has suggested that the left prefrontal cortex, particularly the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (DLPFC), plays an important role in decision making under uncertainty (Duncan and Owen, 2000). However, the causal relationship between these regions and decision making is yet to be fully understood []. The aim of this study was to investigate the effects of high-definition transcranial direct current stimulation HD-tDCS, administered either over the OFC or the DLPFC, on decision making under uncertainty, with a design that was balanced in terms of sex.

A total of 187 college students (96 females, with an average age of 20.37 ± 1.78 years) were recruited in this study. We employed a single-blind, between-subject design with two factors: sex (male vs. female) and stimulation (left OFC, left DLPFC, vs. Sham). The anodal electrode for stimulation over the left OFC was placed over Fp1 in accordance with the international 10–20 EEG System [], with the four return (cathodal) electrodes positioned at Fpz, AF3, AF7, and above the left eyebrow (Fig. 1A). For stimulation over the left DLPFC, the anodal electrode was placed over F3 and the four return electrodes were set at F5, AF3, FC3, and F1 (Fig. 1B). For Sham stimulations, one of the above protocols was randomly chosen, with stimulation ramped up for 30 seconds and then turned off. The protocol of this experiment was approved by the local Institutional Review Board.

The IGT performance was evaluated using two types of indexes: the IGT score and parameters generated by the Prospect Valence Learning (PVL) model. The IGT score was calculated by subtracting the total number of disadvantageous deck selections from the total number of advantageous deck selections (i.e., C + D - A - B) []. The IGT scores of the first 40 trials and the last 60 trials were used to evaluate decision making under ambiguity and decision making under risk, respectively []. The PVL model [] was employed to analyze the IGT, taking into account the shape parameter α (0 < α < 1, where lower values signify greater subjective utility meaning gains and losses are subjectively equal); the loss aversion parameter λ (0 < λ < 5, where higher values indicate greater loss aversion, meaning losses are weighted more heavily than gains); the recency parameter A (0 < A < 1, where higher values denote greater reliance on recent feedbacks); and the consistency parameter c (0 < c < 1, where higher values denote greater decision consistency).

A two-way ANOVA on the total IGT scores revealed a significant main effect of stimulation (F (2, 181) = 3.12, p = 0.047, ${\eta }_p^2$ = 0.03), as well as a significant interaction between stimulation and sex (F (2, 181) = 3.15, p = 0.045, ${\eta }_p^2$ = 0.03). However, there was no main effect of sex (F (1, 181) = 0.01, p = 0.910). Anodal stimulation over the left DLPFC was found to increase the IGT scores (Fig. 1C) compared to both the stimulation over the OFC (p = 0.039) and the Sham stimulation (p = 0.024). In males (Fig. 1D), there was no significant main effect of stimulation (F (2, 88) = 2.27, p = 0.109), while in female, there was a significant main effect (F (2, 93) = 4.07, p = 0.020, ${\eta }_p^2$ = 0.08). Subsequent analysis revealed that the DLPFC group showed significantly higher IGT score than participants in the OFC group (p = 0.005) with Sham group in the middle (Fig. 1E). Analysis of the IGT score in the first 40 trials revealed no significant main effects or interactions (all Fs < 0.84, ps > 0.134). However, when examining the IGT score in the last 60 trials (i.e., decision making under risk), a significant main effect of stimulation (F (2,181) = 3.85, p = 0.023, ${\eta }_p^2$ = 0.04) and a significant interaction between stimulation and sex (F (2,181) = 2.55, p = 0.610, ${\eta }_p^2$ = 0.001) were observed, though there was no main effect of sex (F (1,181) = 0.26, p = 0.610). Post-hoc multiple comparisons indicated that the DLPFC group performed significantly better than the OFC group (p = 0.028) and the Sham-stimulation group (p = 0.012) when making decisions under risk. Moreover, males in the DLPFC group had higher IGT scores than those in the Sham group (p = 0.034) while females in the DLPFC group had significantly higher IGT scores than those in the OFC group (p = 0.006). These results showed that sex played an important role in the effectiveness of tDCS on the IGT, particularly in the risky decision phase.

The Kruskal-Wallis one-way ANOVA and Mann-Whitney U test were employed to conduct nonparametric tests on the parameters yielded by the PVL model, given that they did not follow a normal distribution. Results showed that there were no significant differences on all parameters (ps > 0.244) but the shape parameter α (Fig. 1F) (p = 0.045): the OFC group scored higher than the DLPFC (p = 0.021) and Sham groups (p = 0.050). Similar conclusion was reached when the data was separately analyzed for males (Fig. 1G) and females (Fig. 1H).

Results showed that anodal HD-tDCS applied over the left DLPFC resulted in higher IGT scores for all participants, and particularly for females. Anodal HD-tDCS applied over the left OFC appears to increase sensitivity to gain or loss. This implies that the left OFC and DLPFC have distinct functions in decision making, and that sex modulates this process. The questionnaire followed this single-blind design revealed that participants experienced comparable side effects of tDCS regardless of the DLPFC, OFC and sham conditions; however, future experiments should incorporate a double-blind design.