Unraveling Anhedonia

How ketamine can work against depression

4. July 2022 by Lisa Kiesenhofer
When aesthetic pharmacology merges with clinical imaging: Julia Crone from the University of Vienna and her team in collaboration with Rupert Lanzenberger from the Medical University of Vienna are investigating how psychedelic drugs can help people who are not able to feel joy and excitement.
A joint research project between the disciplines of medicine and psychology: Julia Crone and her team want to find out how intense joy is represented in the brain. This structural MRI image is an example of how activity of specific brain networks can be visualized using fMRI. The colors show the different structures of the brain. © Med Uni Wien

Imagine the following: music fills the room, you feel the beat and are touched by the lyrics. Your heartbeat accelerates, goose bumps begin to raise. A lot of people are able to feel strong emotions while listening to their favourite music. But there are also people who cannot really feel excitement or joy. This condition is called anhedonia and can be a symptom of schizophrenia or depression. Psychological neuroscientist Julia Crone from the University of Vienna unravels the mystery behind these experiences.

Julia Crone explains: What is anhedonia?

"My team is interested in understanding how the brain creates intense feelings of joy. Imagine Christmas, for example: You are a child, waiting in front of the closed door. Finally, it opens and you see the lit Christmas tree and all the wrapped presents and you are filled with joy. Such feelings occur in all kinds of settings and in response to very different types of stimulation, e.g. music. But some people are not able to feel such strong feelings of joy. Some never feel joy at all and this condition is called anhedonia."

Her latest research project – unraveling the aesthetic mind in anhedonia  – brings together two previously strictly separate areas of research: empirical aesthetics and pharmacological/clinical imaging. In this inter-university cluster project, the University of Vienna and the Medical University of Vienna pool acquired knowledge and share expertise: The aim is to understand how ketamine can influence brain activity and cause strong hedonic experiences and, therefore, help people with anhedonia.

Complexity and variety of human brains

Before explaining the details of the experiment itself, Julia Crone illustrates the complexity and variety of human brains with a metaphor: "Imagine riding your bike through a big city– if there is a lot of chaos, every vehicle will move randomly, bump into each other and no one would get anywhere. On the other hand: If everyone went in the same direction, it would be very structured and also very unfunctional." Most people feel comfortable when there is a balance between these two extremes – the so called "edge-to-chaos critical point". This marks the point in which any system, whether city traffic or the brain itself, is most effective.

Julia Crone explains: What is ketamine?

Ketamine has been originally established as an anesthetic agent for surgeries and has pleiotropic effects, meaning it affects various receptor types and cellular processes increasing neuroplasticity. At the subanaesthetic level, ketamine causes a dissociative and hallucinogenic state which has led to an increasing use worldwide as a recreational drug. In such a low dose, ketamine enhances the hedonic tone and shows rapidly acting and highly effective antidepressant properties, even in treatment-resistant depression.

The COVID-19 pandemic and its social consequences are examples of drastic events which can cause an imbalance between chaos and structure. Julia Crone puts her research in this current social context, "Around the globe, people have increasing problems with depression or anxiety due to the COVID-19 pandemic. At the same time, the pandemic has made people become more aware of depression-like symptoms as a social challenge. This has also a positive effect: more and more people are opening up to talk about depression.

Experiment with ketamine and self-chosen music

Julia Crone’s research project started in 2021 – right in the middle of the pandemic. The scientists decided on the following design for their experiment: About 60 participants will be divided into two groups: people who suffer from anhedonia and people who are able to have strong hedonic experiences. The first part of the experiment consists of health checks, during which the participants’ psychological condition is examined.

Next, the participants are assigned to either group. The participants will choose their own music, which is played during the experiment. In the first phase, both groups will receive a placebo. In the second phase, a subanaesthetic amount of ketamine will be administered to the participants in both groups (or vice versa in a randomised order).

Psychedelic drugs against depression and schizophrenia

Julia Crone, her research team, and collaborators including MDs, computational scientists and psychologists are not the first ones to research the effect of ketamine on the brain. EEG/MEG - electroencephalogram/magnetoencephalography - studies suggest that the use of psychedelics increases the complexity of brain activity. "First of, all our study wants to show whether there is a link between increases in brain complexity and hedonic experiences," Julia Crone explains her first research thesis, "The last and more specific research question is whether ketamine actually increases the level of the hedonic experience and  the level of brain complexity.

Julia Crone explains how the reactions are measured during the experiment: "We test the strength of a hedonic experience using physiological and behavioural measures." The participants rate their own behavioural response to the music on a scale of how excited or joyful they feel. Meanwhile, their brain level – how the brain responds physically – is measured by means of functional Magnetic Resonance Imaging (fMRI). Julia Crone adds an insight into possible future results: "So, we actually expect the second group (people who suffer from anhedonia) to have no or not very strong hedonic responses to the music which then increase with ketamine".

Semester question: What shapes human behaviour?

Julia Crone: "The structure of the brain within its native space has evolved in millions of years. This and hedonic experiences are the driving forces of our behaviour. In the face of our fast-changing reality, in which not only the quality but also the quantity of interactions with other people has drastically changed, we are struggling to keep up with the fast pace in developing appropriate coping mechanisms. Our research assumes that the brain, in order to maintain a healthy balance of hedonic responses in everyday life, requires a critical level of complexity and variability. This so-called edge-to-chaos critical point marks the optimal balance at which a system is effectively running. Our project aims to identify the links between this optimal balance of stimulation, the emergence of aesthetic experiences and the lack thereof to tackle the big challenges of modern life."

More inforamtion about the semester question. This content is only available in German.

Research that improves mental health issues

Whether the scientists’ thesis is right will only be revealed in about three years. That is the anticipated duration of the experiments. “I do a lot of interdisciplinary research with MDs, with medical and clinical people, obviously, but also with people from computational informatics and computational science. Sometimes this interdisciplinarity makes things more difficult because we do not speak the same language. But it opens up so much more," Crone explains.

The preparations are just about to be completed: Soon the first control subjects will take part in the experiment. "I am excited for this study to start, because this is not only interdisciplinary research, but also has a very hands-on approach. I feel that research in the clinical sector is very effective because we are actually helping people concerning mental health issues." Thus, the upcoming ketamine experiment may result in a huge medical and scientific breakthrough.

© Christian Valuch
© Christian Valuch
Julia Crone is Senior Scientist at the Vienna Cognitive Science Hub at the University of Vienna, an interdisciplinary research network of Cognitive Science in Vienna and heads the Crone Neurocognition Lab.

She and her lab is interested in complex interactons, network dynamics, as well as intense conscious experiences.