Impact of 5-HT Dysfunction on Controllability Estimation and Cognitive Processes
Context
According to the WHO (World Health organization), one in five individuals will experience a major depressive episode (MDE) during their lifetime. Although antidepressants (AD) are currently the gold standard treatment for MDE, less than 40% of patients respond positively to the first prescribed AD, and a complete clinical response is often only observed after several weeks of treatment. Identifying biomarkers of response to AD treatment could allow clinicians to quickly identify patients for whom treatment may not be effective, thus improving their care.
To achieve this goal, it is essential to better understand the underlying cognitive mechanisms of depressive disorders. Like many other species, humans are very sensitive to the causal influence of their actions on their immediate surroundings and they tend to integrate this causal influence (or its absence) over time, thereby allowing them to estimate the overall control that they can exert over their environment. Distortions of control perception could be a clinical sign of depression and converging evidence indicates that serotonin (5-HT) is involved in the perception of controllability, but the nature and functional significance of this involvement remain poorly understood.
Hypothesis and aims
- We hypothesis the existence of a difference in the perception of control between depressed patients and healthy controls. We also believe that blocking 5-HT reuptake by using SSRI (Selective serotonin reuptake inhibitors) treatment may attenuate these controllability differences between the two groups.
- Our primary aim is to demonstrate a controllability estimation difference between depressive patients (prior to treatment initiation) and healthy participants. We also aim to identify how serotonergic antidepressants influence perception of control, reward-based learning, and the capacity to make predictions.
Methods
The participants meet with a psychiatrist involved in the study who confirms the diagnosis and eligibility of the patient.
Our study is non-interventional (No placebo used), and the enrolled patient will be presented with two versions of the study:
- Neuroimaging version (Figure 1-A):
On Day 0 (D0), there will be an initial session at the Vinatier Hospital in Bron involving an MRI (Magnetic Resonance Imaging) and MEG*(magnetoencephalography) examination.
During the MEG examination, participants will undergo cognitive tasks (estimated duration of 3 hours and 30 minutes):
1/ The exploration and prediction task**.
2/ Learning task associating images with motor responses.
3/ Short- and long-term memory task.
4/ Navigation and prediction tasks.
Later on, the same day, the patient starts the antidepressant medication.
On Day 3 (D3) and Day 14 (D14), participants will undergo online sessions with behavioral tasks (estimated duration of 20 and 15 minutes respectively).
On Day 56 (D56), a second MEG session will take place (estimated duration of 2 hours and 30 minutes). A final interview with the psychiatrist-researcher is planned.
- Behavioral version that can be completed entirely online (Figure 1-B):
Based on psychometric, demographic evaluations, and questionnaires probing a range of psychiatric symptoms (Depression, anxiety, OCD, Stress, attentional disorders), as well as four different cognitive paradigms: Controllability estimation task and a humanized version of the three-port search task, an inverse learning task, and a two-step decision-making task.
On Day 0, the first online session (estimated duration of 75 min), later on, the same day, the patient starts the antidepressant medication.
On Day 3, the second online session (estimated duration of 20 min).
On Day 14, the third online session (estimated duration 15 min).
On Day 56, last online session (estimated duration of 60 min).
With a final interview with the psychiatrist-researcher.
*MEG is non-invasive and poses no known physiological risk. There will be 3 coils in the MEG that allow for head movement tracking by sending a small signal detected by the MEG. The most common constraint here is also claustrophobia, which may be due to the confined space in which the examinations are conducted: a room of about 12m2. Participants who are at physical or psychological risk from MEG will be excluded. Participants are free to leave the MEG, their "headcast," and the room at any time. The MEG will be equipped with a microphone to signal if the participant wishes to leave the room (a video system is also present).
MRI is a technique used daily in clinical practice, often recommended in the care pathway for depressive patients. The MRI will be performed without contrast agent and will therefore be non-invasive.
**The exploration and prediction task (Figure 2) aims to study learning and decision-making processes using exploratory trials followed by predictions to assess rule understanding and the ability to estimate controllability of situations. During the task, participants first perform exploratory trials to familiarize themselves with task rules. In each exploratory trial, two identical geometric shapes are presented, and the color of each shape indicates which action corresponds to each button (left or right). After a delay of 1.5 seconds, an emergency signal appears, indicating the need to choose an action. Transitions to new states are determined by one of four specific task rules. Once exploratory trials are completed, participants make predictions about actions to take in specific situations. Prediction pairs always involve choosing between two possible actions for a given state. Participants receive feedback on their predictions in most trials, helping them learn task rules without deducing whether the rule was controllable or not.