Bipolar symptoms and lithium treatment affect neural signatures of adaptation of risk-taking to past outcomes during reward-guided decision-making

Introduction Mood instability in bipolar disorder (BD) is poorly understood. Here we examined cognitive and neural mechanisms related to these fluctuations and how they are changed with the mood stabilizer lithium. Methods We recruited volunteers with low (n=37) or high (n=40) risk of BD (using the Mood Disorder Questionnaire, MDQ). We also recruited patients with BD who were assigned (randomized, double-blind) to six weeks of lithium (n=19) or placebo (n=16) after a two-week baseline period. Participants completed mood ratings daily over 50 (healthy) or 42 (BD) days, as well as a risky decision-making task and one functional magnetic resonance imaging session. The task measured adaptation of risk taking to past outcomes (increased risk aversion after a previous win, ‘outcome history’). Results While the low MDQ group was risk averse after a win, this was less evident in the high MDQ group and least so in the patients with BD. Neurally, ‘outcome history’ was linked to medial frontal pole activation at the time of the decision. Corresponding to the behavioural effect, this activation was reduced in the high MDQ vs. the low MDQ group. While lithium did not reverse the pattern of BD in the task, it changed reward processing in the dorsolateral prefrontal cortex. Discussion Healthy participants’ modulation of risk-taking in response to reward outcomes was reduced by risk of BD and BD. These results provide a model for how reward may prime escalation of risk-related behaviours in bipolar disorder and how mood stabilising treatments may work. ### Competing Interest Statement JS, PP, NN, LZA, NK, JG, MFSR report no biomedical financial interests or potential conflicts of interest. CJH has received consultancy payments from P1vital, Lundbeck, Compass Pathways, IESO, Zogenix (now UCB). PJH reports receiving an honorarium for editorial work for Biological Psychiatry and Biological Psychiatry Global Open Science. ACN is non-executive director at the Oxford Health Foundation Trust. KEAS has received consultancy payment from Yale University. ### Clinical Trial ISRCTN91624955 ### Funding Statement The study was funded by a Wellcome Trust Strategic Award (CONBRIO: Collaborative Oxford Network for Bipolar Research to Improve Outcomes, reference No. 102,616/Z). JRG, CJH, PJH and KEAS are supported by the Oxford Health NIHR Biomedical Research Centre. MFSR is funded by the Wellcome Trust (221794/Z/20/Z). The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z). JS has been funded by the Institut National de la Sante et de la Recherche Medicale, the Biotechnology and Biological Sciences Research Council (BB/V004999/1, Discovery Fellowship) and Medical Research Council (MR/N014448/1, Skills Development Fellowship). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Oxford University Ethics Committee gave ethical approval for this work (MSD-IDREC-C2-2014-023). The South Central - Oxford A Research Ethics Committee gave ethical approval for this work (15/SC/0109). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.