Noradrenaline, Acetylcholine and Dynamic Learning in Healthy Humans
Condition: Healthy
Study type: Interventional

Summary: 
      The aim of this study is to characterize the role of central norepinephrine and acetylcholine
      on reward and emotion related information processing in healthy volunteers using behavioural
      tasks and pupillometry (with eye tracking equipment). The pharmacological compounds used in
      the study (reboxetine and rivastigmine) are used as tools to manipulate these systems rather
      than to treat patients. The aim of the study is not to study the clinical effects,
      pharmacodynamics, adverse reactions, absorption, distribution, metabolism or excretion of the
      drugs. Further, the population studied is non-clinical, the drugs are not administered in a
      therapeutic dosing regimen (only a single dose of study drug will be administered) and the
      investigators do not measure clinically significant outcomes.
    

Detailed description: 
      Background: Previous research has shown that human learners are able to encode the
      probabilities of positive and negative outcomes in parallel, and adjust their learning
      behaviour to the information content of positive and negative outcomes (Pulcu and Browning
      2017). In reinforcement learning tasks, the volatility (also known as unexpected uncertainty
      arising when the environment changes suddenly) of outcomes directly influences how
      informative the outcomes are perceived to be (Behrens, Woolrich et al. 2007). Previous
      studies consistently shown that human participants use a higher learning rate while learning
      from outcomes with high volatility (Behrens, Woolrich et al. 2007, Browning, Behrens et al.
      2015, Pulcu and Browning 2017). Another source of uncertainty is expected uncertainty, which
      arises from naturally varying outcomes (e.g. day to day changes in temperature). Different
      sources of uncertainty in the environment are argued to be associated with the activity of
      different neurotransmitter systems in the human brain (Yu and Dayan, 2005)(Angela and Dayan
      2005). For example, outcome volatility (unexpected uncertainty) is thought to be associated
      with the activity of the central norepinephrine (NE) system, whereas outcome variation
      (expected uncertainty) has been linked to the cholinergic (ACY) system.

      Studies using pupillometry (a non-invasive way of inferring central norepinephrine activity
      in the human brain) showed that pupil size is associated with the volatility of outcomes
      during reinforcement learning tasks (Browning, Behrens et al. 2015, Pulcu and Browning 2017).
      However, pupil size can also be influenced by the activity of other neurotransmitters
      including acetylcholine limiting the degree to which these results can be attributed to the
      NE system. Further, previous human studies have been associational in nature and thus the
      causal role of the NE and ACY systems in human learning under uncertainty have yet to be
      tested. The current study will address this knowledge gap by investigating how administering
      a single dose of the norepinephrine reuptake inhibitor reboxetine or cholinesterase inhibitor
      rivastigmine influence choice behaviour and pupillary correlates of human reinforcement
      learning.

      Study Structure: All participants will be recruited via the recruitment pipeline described
      below. The randomisation procedure used will treat participants as if 2 parallel studies were
      running: a reboxetine vs. placebo and a rivastigmine vs. placebo study. Researchers will
      assign participants to either the reboxetine or rivastigmine arm (NB researchers will not be
      blind to this allocation although participants will be). Both studies will randomise
      participants in a 1:1 ratio, stratified by gender, to either the active drug or placebo (NB
      both researchers and participants will remain blind to this allocation). This will result in
      an overall group size for the reboxetine:rivastigmine:placebo groups of 30:30:60 (with
      participants randomised to placebo being specifically associated with the reboxetine or
      rivastigmine group). The rationale for this approach is that, while study procedures are
      identical for all participants, the investigators are addressing 2 separate questions in this
      study (the effect of NE manipulation and the effect of ACY manipulation on learning) which
      are more straightforwardly assessed using two, separate, placebo controlled comparisons
      rather than a larger three group study.
    

Intervention name(s): Reboxetine; Rivastigmine; Placebo oral tablet
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Single dose used to increase central norepinepherine; Single dose to increase central acetylcholine; Single dose as control condition
Intervention MeSH terms: Rivastigmine; Reboxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Three group parallel design
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science