Effect of lithium administration on brain activity under an emotion regulation paradigm in healthy participants: a functional magnetic resonance imaging study

Abstract

Rationale: Emotion regulation (ER) difficulties have been previously described in bipolar disorder (BD). Whilst lithium has been shown to be effective in the treatment of BD, the mechanisms underlying lithium's effect on mood stabilisation remain unclear.

Objectives: Unravelling lithium's effect on psychological processes impaired in BD, such as ER, could address this translational gap and inform the development of new treatments.

Methods: This study investigated the neural effects of lithium (800mg) on ER in 33 healthy volunteers in a double-blind between-groups design, randomised to lithium (n=17) or placebo (n=16) for 11 days. At treatment completion, participants underwent 3-Tesla fMRI scan whilst performing an ER task.

Results: Reappraisal reduced negative affect across groups and led to the expected increase in frontal brain activity. Participants receiving lithium showed (1) decreased activation in prefrontal and posterior parietal cortices and connectivity between the fronto-limbic network (Z>2.3, p<0.05 corrected); and (2) increased activity in the right superior temporal gyrus (Z>3.1, p<0.05 corrected) and connectivity between the right medial temporal gyrus (MTG) and left middle frontal gyrus (Z>2.3, p<0.05 corrected) during reappraisal. Further effects of lithium were found in response to negative picture presentation, whereby an anticorrelation was found between the left amygdala and the frontal cortex, and greater connectivity between the right MTG and the bilateral medial prefrontal cortex extending into the paracingulate gyrus, compared to placebo (Z>2.3, p < 0.05 corrected).

Conclusions: These results show a potential effect of lithium on ER through its effects on activity and connectivity, and further elaborate the neural underpinnings of cognitive reappraisal. Future work should investigate longer term effects of lithium on ER in BD, ultimately benefitting the development of novel and more effective treatments.

Keywords: Emotional processing; Emotional regulation; Lithium; Task fMRI.

Fig. 1

Whole-brain analysis results. a, b Main effect of task: significant increased activation in brain areas including the bilateral ACC, anterior PFC, supplementary motor cortex, dmPFC, dlPFC, vlPFC, lateral OFC, insular cortex, temporoparietal junction, superior and middle temporal gyrus, lateral occipital cortex, occipital cortex, cerebellum, thalamus, pallidum and caudate, and left supramarginal gyrus when reappraising compared to maintaining across groups. c Group × Task Interactions at Z>2.3. Significant increased activation in the left angular gyrus towards supramarginal gyrus, d left anterior prefrontal cortex, and e right superior frontal gyrus when reappraising compared to maintaining in placebo compared to lithium. In addition to the parameter estimates for the reappraise greater than maintain contrast, the parameter estimates for both maintain and supress vs baseline were also extracted for completeness. Error bars represent SEM

Fig. 2

Whole-brain connectivity analysis. Main effect of task (Z > 2.3, p < 0.05 corrected). a Right amygdala’s activity (pink) significantly correlated with deactivation in a cluster spanning the left lateral occipital cortex (red), the right lateral occipital cortex (purple), and right precentral gyrus extending into middle frontal gyrus (BA6+9; blue) when reappraising compared to maintaining, across groups. b Right vmPFC (green) significantly correlated with deactivation in a cluster covering the left medial PFC to the vmPFC (green) when reappraising compared to maintaining, across groups. Left vmPFC (red) significantly correlated with deactivation in a cluster covering the left vmPFC towards the medial PFC (red) when reappraising compared to maintaining, across groups. c Right vlPFC’s (blue) activity significantly correlated with deactivation in the right precentral gyrus extending into central opercular cortex, insular cortex, and putamen (yellow). d Right MTG’s activity (red) significantly correlated with deactivation in four clusters spanning the bilateral superior frontal gyrus towards supplementary motor cortex and ACC (red), bilateral precuneous cortex extending into pre-central gyrus (purple), the left precentral gyrus towards the middle frontal gyrus, and the bilateral superior frontal gyrus (green)

Fig. 3

Whole-brain connectivity analysis. Group by task interaction, Z>2.3, p < 0.05 corrected. a There was significantly greater connectivity between the right MTG (red) and the left middle frontal gyrus (covering BA 8, 6, and 9; orange) in the lithium group compared to placebo during reappraisal versus maintain. b There was a significantly greater connectivity between the right vlPFC (blue) and the right caudate, extending into the right frontal pole/anterior PFC and ACC frontal opercular cortex/insula (BA13; orange) in the placebo group compared to the lithium group when reappraising versus maintain

Fig. 4

Whole-brain connectivity analysis. Main effect of group (Z > 2.3, p < 0.05 corrected). a There was significantly greater negative connectivity between the left amygdala (blue) and bilateral frontal cortex (orange) for the lithium group compared to the placebo group in response to aversive pictures (mean of reappraise and maintain). b There was significantly greater connectivity between the right MTG (red) and the bilateral medial PFC (yellow) during overall negative picture blocks (mean reappraise and maintain) in the lithium group, compared to placebo. Error bars represent SEM