Ultrasound brain stimulation: studying emotions and decision-making in the human brain

Understanding how the human brain makes decisions, processes emotions and regulates mood is one of the central challenges of contemporary neuroscience.

In recent years, new technologies have begun to offer researchers the possibility to study deep brain circuits with increasing precision. Among them, ultrasound brain stimulation is emerging as a promising tool to investigate the neural mechanisms underlying complex human behavior.

Imagine a simple everyday situation. It is the beginning of the year and, like many people, we decide to sign up for a gym course. We browse gym websites looking for the option that suits us the best. We compare prices, discounts and offers, we choose one course and go for subscriptions, but eventually we find out that they are closed.

Hence, we need to change the course choice. However, we will remember our first preference for future decisions that can guide us to go for it if it’s still worthwhile and subscriptions will open again.

Why studying deep brain circuits remains a challenge

In all cases, every decision we make emerges from a complex interplay of memory, emotion and cognition, processes that originate deep in the brain and shape our daily actions and who we are. Yet causally identifying the neural circuits underlying these deep brain processes down to sub-millimetric resolution remains a major challenge for modern neuroscience.

This is despite EEG and fMRI, tools that correlate brain activity with behavior, mood and cognition, but cannot establish causality. To demonstrate causal links, researchers must be able to directly perturb brain activity and measure the resulting behavioral changes. At the same time, non-invasive methods with sufficient spatial precision and the ability to target deep brain regions are still limited.

It is within this scientific and technological gap that Dr. Davide Folloni, who received an ERC Starting Grant in 2025, positions his research. At his newly established laboratory at Vita-Salute San Raffaele University, he aims to develop novel ultrasound brain stimulation techniques to address the following questions:

• Can we non-invasively and focally modulate deep human brain circuits regulating decision-making, learning and mood?

• Can we use these techniques to understand, with high precision, the neural underpinnings of complex behaviors?

Can we translate these approaches to the clinic and use them to treat neurological and psychiatric disorders?  

Ultrasound as a tool for causal neuroscience

With a background in Clinical Psychology and Neuroscience, Dr. Folloni has long been interested in neural mechanisms underlying human behavior. «Why we make certain choices, how emotions fluctuate across lifespan, and how social context shapes who we become: I find all these questions fascinating», he explains.

To causally probe complex brain–behavior relationships, during his PhD at the University of Oxford Dr. Folloni developed protocols of transcranial focused ultrasound stimulation (TUS), an emerging method of non-invasive brain stimulation.

Compared with established techniques such as transcranial magnetic stimulation or electrical stimulation, TUS offers two key advantages: greater penetration deep in the brain and higher spatial resolution.

This technology can selectively target focal and subcortical brain regions, including the amygdala, the basal ganglia and deep orbital areas, and, when combined with fMRI, reveal how local perturbations propagate across distributed brain networks.

Previous research on decision-making in the brain

In previous works, Dr. Folloni and colleagues used a combination of fMRI and TUS to study associative learning and counterfactual choice, that is, how the brain learns what the best choice is and how it uses this learning to guide future decisions.

In these studies, the researchers investigated the contribution of three different brain areas involved in decision-making: the hippocampus, the lateral orbitofrontal cortex and the anterior cingulate cortex. They observed that after learning to associate each available option with its outcome, our brain makes decisions while retaining the memory of all possible alternatives and storing them for future evaluation, even when such options are not currently available.

fMRI imaging correlated activity in the hippocampus with maintaining the memory of learned options, activity in the anterior cingulate cortex with evaluating whether behavior should change to align with existing values, and activity in the lateral frontal cortex with learning, planning and updating decisions.

Moreover, by using transcranial focused ultrasound to interfere with activity in the anterior cingulate cortex, the researchers demonstrated the causal link between activity in this specific brain region and the evaluation of alternative choices, including those that are not immediately available.

How deep brain circuits guide everyday decisions

Revisiting the gym example introduced at the beginning, different brain regions contribute in complementary ways to this decision process. The hippocampus plays a key role in representing memories of the various course options we encountered while browsing gym websites.

When the preferred course becomes available again, regions such as the anterior cingulate cortex become important for evaluating whether switching behavior is worthwhile, weighing past preferences, current goals and contextual constraints.

These evaluations interact with prefrontal cortical processes involved in planning and implementing actions, ultimately guiding the decision to subscribe to the preferred option.

Such choices do not rely on a single brain area. Instead, they emerge from coordinated interactions across distributed deep brain circuits that support memory, valuation and cognitive control. Understanding how these circuits interact is one of the central goals of contemporary neuroscience and an area where ultrasound brain stimulation may provide new insights.

From brain research to clinical applications

The ERC-funded project that Dr Folloni is now launching at UniSR builds on these preliminary observations to study the neural mechanisms underlying decision-making and mood regulation by applying transcranial focused ultrasound stimulation in humans.

Notably, many of these circuits converge in deep brain regions such as the amygdala and deep cortical structures including the anterior cingulate cortex, areas that TUS can selectively target.

«Initially, we will use TUS in healthy participants to understand how targeted modulation of specific circuits alters behavior», says Dr. Folloni.

Towards new non-invasive therapies for brain disorders

In clinical neuroscience, causal interventions on deep brain circuits usually involve patients undergoing invasive treatments whose brains have already been altered by disease and long-term medication. One example is deep brain stimulation used in Parkinson’s diseaseNon-invasive ultrasound, by contrast, allows researchers to probe the same circuits in healthy brains in a safe way.

This approach allows scientists to study how natural variability in circuit function relates to behavior, and how transient modulation may push the system toward or away from pathological states.

The project integrates TUS with MRI, computational modeling, behavioral tasks and autonomic measurements. The goal is not only to detect changes, but to map how specific circuit modulations propagate across neural systems and translate into behavior.

In the long term, this research follows a translational trajectory: from causal mapping in healthy individuals to hypothesis-driven studies in patient populations, and ultimately to the development of new therapeutic strategies that could complement existing non-invasive brain stimulation approaches.

«In this sense», Dr. Folloni concludes, «San Raffaele offers a unique ecosystem where close interactions between research and clinical practice, combined with technological hubs like Neurotech, the neurorehabilitation center jointly established between UniSR and San Raffaele Hospital and directed by Prof. Massimo Filippi, create fertile ground for innovation that can genuinely impact patients».