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Pioneering focused Ultrasounds as a new non-invasive deep brain stimulation for a causal investigation of empathy related brain processes in moral learning and decision making

Periodic Reporting for period 3 - HelpUS (Pioneering focused Ultrasounds as a new non-invasive deep brain stimulation for a causal investigation of empathy related brain processes in moral learning and decision making)

Reporting period: 2021-07-01 to 2022-12-31

As the COVID time reminded us, our life is a constant trade-off between the benefits and costs for self and those of others. In order to decide what action to take, we need to attribute values to the options at stake.
Reinforcement learning theory formalizes how people learn action-outcome values. Our feelings during the action-outcome will determine the value for that action. If we feel the same when we encounter the same action-outcome, we reinforce the initial value, if instead the action results in different outcomes, we will update the initial value to match how we now feel.
Attributing a value to an action when its outcome affects someone else is less direct. Years of research on how we perceive other people’s states suggest we have two complementary ways to guess how others feel. The cognitive route collects the information we have about the other to reason about the other. The affective route, suggests that the emotional state of the other, conveyed by their facial expression, posture, etc., resonates with the state we would feel when in a similar way.
People tend to avoid situations in which they directly face people in distress more often than situation in which they are only informed about the state of the other. What is then special about witnessing what happens to others? How does seeing what happens to others affect our evaluation process? Would being a direct witness make me learn faster the consequences of my actions, or more pro-social? How consequences for myself and for others are integrated and compared in my decisions?
In order to operationalize these questions, we developed a reinforcement learning paradigm in which participants need to learn which of the two options gives a higher monetary reward for the participant and higher physical pain for the other, and which gives a lower monetary reward for self and lower pain for the other. By changing the way the outcome is displayed (video of the person in pain or text), the gender of the pain-receiver, and action-outcome probabilities we will characterize the learning processes of such complex decisions. Imaging data during the task will identify the circuits involved, and neuro-modulation methods will reveals the role each node of the circuit plays. This latter step will be fundamental in order to test the hypothesis that affective empathy is necessary to feel with the other and to update the value we associate to our own actions. Unfortunately, many of the areas involved in affective empathy are difficult to non-invasively perturb, making testing causality almost impossible, leaving most of what we know about empathy lying on correlations.
Part of this grant therefor focuses on the development of a new non-invasive neuro-stimulation method that would allow to perturb such deep regions. This method uses ultrasounds, which differently from available methods, can be focused and used to selectively interfere with any region of interest, independently from their location. As the mechanisms of action of focus ultrasounds is little known, we are investigating such mechanisms in rodents. Calcium imaging is combined with immuno-histology to visualize and characterize activated cells. This research line will hopefully give us a tool to establish the causal link between empathy-related phenomena and our altruistic or antisocial behavior in humans. Finally, the effect of ultrasounds, will also be measured by ultrasound imaging, which relies on changes in blood flow, more directly comparable with what normally people measure in human participants with fMRI.
Three behavioral experiments and one fMRI, were run from the beginning of the project. Preliminary results indicate that people vary in the way they learn this symbol-outcome associations. Some individuals are motivated by the money choosing more often the option that brings higher monetary reward to the self at the expensive of more pain to the other. Others value the pain of others more than the money for self. A third group remains neutral without a clear preference. The reinforcement learning models indicate that our individual preference for the money or the pain exert it influences at the moment in which we are directly confronted with the outcome of our actions. No gender differences where observed so far.
Regarding the ultrasound projects, we first brought the technique to the lab, then we collected calcium imaging data of four mice while stimulating with ultrasounds using different stimulation protocols. Preliminary results indicate a difference in the cell response-amplitude that depends by the stimulation intensity. With the ultrasound imaging system, we obtain images of a partial volume of the brain of awake mice, and soon we’ll combine imaging and stimulation.
The focus of the project on conflictual choices between self and others expands the use of reinforcement learning models and unravel the brain circuits involved. By letting our participant witness the reaction of others (instead of offering numerical outcomes) we hope to understand the mechanism of real life situations.
We developed a mathematical model that predicts the time course and individual variability of choices while participants witness the consequences of actions on others and themselves. We then showed that the network associated with empathy contain signals that conform to the predictions of our mathematical models (preprint at https://doi.org/10.1101/2020.06.10.143891).
By the end of the project we expect to have a more extensive understanding of the impact of witnessing, rather than knowing, the consequences of our actions, and of other variables such as participant’s or pain recipient’s gender.
To study causality between brain activity and behavior, researchers perturb the activity of a particular regions while behavioral changes are recorded. Unfortunately, the activity of deep brain regions can only be perturbed invasively. Helping the developed of ultrasounds neuro-stimulation will potentially help allowing non-invasive stimulation in deep brain regions in humans.
Our main achievement has been the recording of calcium imaging signals in mouse neurons while applying focused ultrasound stimulation, with significant increases of activity measured while applying the stimulation protocol we hoped would increase brain activity. By the end of the project we aimed at knowing whether certain cell type are more susceptible to ultrasound stimulations than others, and whether the ultrasounds protocol used so far consistently and reliably induces cell activations.
Brain activity is typically measured using different methods in humans and animals: changes in blood flow measured in humans, versus changes in cell activity trough electrical recordings or calcium imaging. Translating result across species is therefore difficult. Increasing literature shows that spiking of neurons and blood oxygenation level are only loosely linked. Combining ultrasound and calcium imaging in rodents this project aims at bridging the gap between the blood flow measurements in humans, and electrical activity in rodents. This will be essential for the understanding of the effects of ultrasound stimulation to a level in which we can understand the effect on neurons and how this should translate into fMRI signal changes in humans.
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