Lithium Effects on Reward Processing and Reappraisal in Healthy Volunteers

Study Overview
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Brief Summary
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Bipolar disorder has been associated with blunted activity in regions associated with emotional processing, such as striatal activity during reward anticipation as well as prefrontal activity during reappraisal. Lithium is the most effective treatment in bipolar disorder. Neurochemical and molecular basis of lithium is well known, but how this translates to mood stabilisation is not understood. This study is designed to address how lithium influences reward and emotion regulation processes in humans.

Detailed Description
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Background: Bipolar disorder is a relatively common psychiatric disorder for which treatment options are limited. The so-called mood stabiliser, lithium (usually in the form of lithium carbonate) is one of the most commonly used treatments for the disorder, and is effective in treating both acute mania and as a long term maintenance treatment. The investigator's understanding of the pharmacological mechanisms by which lithium exerts its actions is fairly well developed, however there is a lack of understanding of the psychological mechanisms. Within this study the investigators will look at two different types of emotional processing, namely reward anticipation/feedback and emotion regulation, to gain more understanding on how lithium exerts its mood stabilising effects. Reward processing: The neural correlates underlying reward anticipation and feedback can be measured with the Monetary Incentive Delay (MID) task, a widely used task for different disorders. Reward anticipation during the MID task has been associated among others, with ventral and dorsal striatum activity. Most critically, bipolar disorder has been associated with blunted reward function of the medial caudate. Reward feedback has been associated with ventral striatum and OFC/vmPFC activity. Emotion regulation: One of the most prominent approaches of emotion regulation is reappraisal . Reappraisal has been shown to consistently activate cognitive control regions and to modulate the bilateral amygdala. Insufficient prefrontal control and reduced downregulation of those prefrontal regions of the amygdala while reappraising negative stimuli has been consistently found in bipolar disorder. Methods: Using a double-blind, parallel-group design, 37 healthy volunteers (male and female) are randomly allocated to a 11 (+/- 1) day lithium administration or a placebo condition. After the intervention period, all participants undergo fMRI testing with the MID task and the emotional suppression task to assess reward processing and reappraisal of negative stimuli. The participants also complete a visual control task (checkerboard task) and several behavioural tasks and questionnaires. Lithium levels are measured at the end of the intervention period. Hypothesis: Based on the literature on bipolar disorder and the mood stabilising effects of Lithium, the investigators expect lithium administration in healthy participants to: Increase caudate activity during reward anticipation Increase activation of prefrontal control regions as well as increase negative connectivity between those regions and the amygdala during reappraisal Fidelity check: significant increases in lithium levels in the lithium intervention group compared to the placebo group.

Official Title
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The Effects of Short-term Lithium Administration on Striatal Reward Processing and Prefrontal Control During Reappraisal in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Lithium
* Other: Placebo - Rayotabs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is willing and able to give informed consent for participation in the study. Subject is between 18 and 55 years of age Subject has a body mass index (BMI) in the range of 19-30 Subjects will be physically fit, as assessed by a physical examination by a medical doctor. if female and of child bearing age must have a negative pregnancy test for inclusion and must be using two forms of effective contraception. Subjects will be fluent English speakers Thyroid stimulating hormone and creatinine will be assessed pre-treatment to ensure that these are within healthy range non or light smoker < 5 cigarettes per day right handed Exclusion Criteria: taking psychotropic medication any past or current axis 1 psychiatric disorder on DSM-IV Any medical contra-indication (for example, conditions that might alter absorption of lithium or which could impact on the safety of the druk for the volunteer, for example impaired renal function as assessed by creatinine levels or impaired thyroid function as assessed by thyroid stimulating hormone levels) Current pregnancy or breastfeeding Current or past history of drug or alcohol dependency Participant in a psychological or medical study involving the medication within the last 3 months Smoker > 5 cigarettes per day Dyslexia Any contra-indication to MRI scanning, for example chance of metal in the body Left-handed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants were randomly assigned to the placebo or lithium group. The two groups were matched in terms of age and gender.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lithium<br>Increasing amounts of lithium for 11 plus or minus 1 day. Day 1: 400 mg at night Day 2: 600 mg at night Day 3-11: 800 mg at night. The lithium intervention was prepared from 200mg Priadel prolonged release tablets. The intervention was provided in blue and white gelatine capsules to be taken orally. | Drug: Lithium<br> <br> * Other names: Lithium carbonate;|
| Placebo Comparator: Rayotabs<br>The placebo intervention was 200mg Rayotabs. The intervention was provided in blue and white gelatine capsules to be taken orally - same as the lithium intervention to maintain blinding. | Other: Placebo - Rayotabs<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| brain response to reward anticipation (MID task, Knutson et al. 2001) | Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). Group differences in the brain response while anticipating a reward (after reward cue) will be compared to the brain response while not anticipating a reward (after no reward cue). The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001). | Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). | 
| Brain response during reappraisal task (Phan et al. 2005) | Participants will perform a reappraisal task (Phan et al. 2005). Trials in which they were asked to either down-regulate negative affect evoked by highly arousing and aversive pictures (e.g., experience naturally) using cognitive reappraisal will be compared to trials where negative affect if maintained. Group differences in brain activation changes during this comparison will be assessed with a specific focus on the prefrontal cortex, as well as on connectivity changes between prefrontal cortex and amygdala during this contrast. | Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| brain activation in response to reward feedback (MID task) | Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). After an inter-trial-interfval of 2000-2500ms, a target is presented during which participants need to press a button on reward and no reward trials. If they respond on time it is a hit, otherwise a loss. Group differences in the brain response while receiving feedback on a hit during reward trials will be compared to the brain response while receiving feedback on a loss during reward trials. The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001). | Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lithium, Reward, Caudate, Reappraisal, Prefrontal cortex, Amygdala