A 7 Tesla Amygdalar-Hippocampal Shape Analysis of Lithium Response in Bipolar Disorder

Thomas L Athey,J Raymond Depaulo,Pamela B Mahon,Kwame S Kutten,Can Ceritoglu,Kara Glazer,J Tilak Ratnanather,Francis Mondimore,Caroline M Nievergelt,Kelly Rootes-Murdy,John R Kelsoe,Fernando S Goes,Daniel J Tward,Peter P Zandi

doi:10.3389/fpsyt.2021.614010

Abstract

Research to discover clinically useful predictors of lithium response in patients with bipolar disorder has largely found them to be elusive. We demonstrate here that detailed neuroimaging may have the potential to fill this important gap in mood disorder therapeutics. Lithium treatment and bipolar disorder have both been shown to affect anatomy of the hippocampi and amygdalae but there is no consensus on the nature of their effects. We aimed to investigate structural surface anatomy changes in amygdala and hippocampus correlated with treatment response in bipolar disorder. Patients with bipolar disorder (N = 14) underwent lithium treatment, were classified by response status at acute and long-term time points, and scanned with 7 Tesla structural MRI. Large Deformation Diffeomorphic Metric Mapping was applied to detect local differences in hippocampal and amygdalar anatomy between lithium responders and non-responders. Anatomy was also compared to 21 healthy comparison participants. A patch of the ventral surface of the left hippocampus was found to be significantly atrophied in non-responders as compared to responders at the acute time point and was associated at a trend-level with long-term response status. We did not detect an association between response status and surface anatomy of the right hippocampus or amygdala. To the best of our knowledge, this is the first shape analysis of hippocampus and amygdala in bipolar disorder using 7 Tesla MRI. These results can inform future work investigating possible neuroimaging predictors of lithium response in bipolar disorder.

Highlights

Bipolar I disorder (BD) is characterized by a relapsing and remitting course and is common, affecting an estimated 1% of the population [1]
Results of this study provide evidence of lateralized morphometric differences in hippocampus in a group of patients with BD who did and did not respond to lithium treatment
We did not find a significant difference in volumes of amygdalae or hippocampi between the lithium responders, non-responders, and healthy comparison participants (HC) groups

Summary

Introduction

Bipolar I disorder (BD) is characterized by a relapsing and remitting course and is common, affecting an estimated 1% of the population [1]. Lithium is a common mood-stabilizing treatment that has been shown to significantly reduce risk of depressive or manic relapse [3, 4]. A limited number of predictors of lithium response in BD have been identified, including clinical and genetic features [6,7,8,9]. Clinical predictors of positive response include an illness pattern of manic episodes before depressive episodes and later age of onset of the disorder. Genome Wide Association Studies (GWAS) have identified genetic variation associated with lithium response, including single nucleotide polymorphisms (SNPs) located in a region containing genes for long non-coding RNAs that regulate gene expression and in the genes SESTD1 and in GADL1 [10,11,12]. Additional suggestive associations of lithium response have been reported with SNPs located in the gene GRIA2 and with microRNAs [13, 14]

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