Dr. Katharina Schmack
MD-PhD Charité, Berlin
Postdoctoral clinician fellowship Charité, Berlin
Research fellowship CSHL, New York
Clinical Group Leader Francis Crick Institute
Growing up in a small town in Germany, Dr. Katharina Schmack never imagined herself as a scientist. Instead, she dreamed of becoming a bohemian intellectual: living somewhere glamorous, dedicating her time to artistic pursuits, and having high-brow discussions with interesting and eccentric people. Her good grades in school and aptitude for science, however, meant she was encouraged from an early age to pursue a career as a medical doctor. And so after graduating high school, with no clear path to achieving the bohemian lifestyle she wanted, she moved to Berlin to complete a medical degree.
While life in Berlin aligned well with her artistic aspirations, she found medical school tedious and boring. She admits spending many sleepless nights in those early years thinking “Oh my god, what have I done? This is not for me!” However, in her fourth or fifth year of medical school, she attended a class on the use of fMRI in psychiatry that completely shifted her perspective. “This technology allows you to look into the brain while people are experiencing emotions and thoughts…To me this seemed like the perfect way to understand what makes us humans, to understand our subjective experiences.” After class, she walked straight up to the professor and asked how she could be involved in this work. Soon after, she decided to pause her medical training and begin writing a doctoral thesis at the Department of Psychiatry at the Charité in Berlin.
Katharina’s PhD work focused on the pharmacological and genetic factors that influence dopamine modulation during different cognitive processes. For example, she used fMRI to investigate brain-wide activity during working memory tasks and in response to reward, both in patients with schizophrenia and healthy control subjects. This work culminated in the discovery that certain brain responses could be linked to a genetic difference (polymorphism) in an enzyme responsible for breaking down dopamine. She found that people with a genetically determined increase in dopamine displayed stronger responses to abstract reward-related cues. That something as subjective as someone’s reaction to rewarding stimuli could be related to something as inherently biological as a polymorphism fascinated her: an overarching theme that would shape much of her work in the years that followed.
After finishing her PhD, Katharina returned to medical school to complete her medical degree and later her specialist training in psychiatry. Despite her initial qualms about medical school, Katharina fell in love with clinical work when she started to work with patients. It was at this point that she first became interested in psychosis. She vividly remembers one of her first patients, a young woman who believed there were hidden cameras in her bedroom that were broadcasting her every movement on the internet. This patient turned out to be experiencing the early stages of multiple sclerosis - an autoimmune condition characterised by the breakdown of the myelin sheath around nerve fibres. Yet again, Katharina was confronted with the realisation that inherently biological processes can translate into bizarre, idiosyncratic, and subjective perceptual symptoms.
Katharina found a potential explanation for these curious patterns of symptoms in a paper by Dr. Paul Fletcher and Dr. Chris Frith. This paper argued that the diverse symptoms of psychosis could be explained by an abnormal inference process. In brief, patients stop successfully integrating incoming perceptual information and instead rely more on their own internal models of the world. As a result, their perception may warp to fit their expectations. Katharina found this argument compelling as it matched her observations of the patient in her care. Critically, it also provided a testable hypothesis to explain the mechanisms underpinning psychotic experiences.
Around this time, one of her colleagues asked Katharina if she wanted to join his research group for a part-time postdoc while completing her residency. She seized this opportunity to investigate the key hypothesis raised by Fletcher and Frith’s paper: do people with psychosis rely more strongly on their expectations? Testing this idea involved some very simple but elegant behavioural experiments. In one study, participants were given a pair of glasses and were told that wearing these glasses would alter their visual perception. In reality, the glasses had no effect on perception whatsoever - they were just normal glasses. Katharina found that people with a tendency towards psychotic experiences were more likely to report an alteration in their perception than those with little or no past psychotic experiences. In a range of these simple perceptual tasks, each testing different kinds of expectation and perception, Katharina repeatedly found that people with a history of psychosis appeared to rely more on their conscious expectations than incoming perceptual information compared to control subjects.
As she continued working as both a clinician and a postdoc, Katharina began to experience some new feelings towards her area of study. Patients with psychosis would come to her for help and she felt frustrated by her inability to provide a good explanation of what was happening to them. “We can give you some drugs that block your dopamine system and then you might get better but we don’t really understand why,” was all she could say. This frustration prompted her to pursue a research fellowship, hoping to develop an understanding of the biological mechanisms underpinning her patients’ experiences. This led her to Dr. Adam Kepecs’ lab at Cold Spring Harbor Laboratory (CSHL).
With her background in clinical psychiatry and Adam Kepecs’ expertise in rodent cognition and experimental neuroscience, they set out to develop a mouse model of hallucination. “I think it’s a perfect example of how different backgrounds can add up to something new,” Katharina reflects. They developed an auditory detection task in which mice were required to indicate using one of two nose ports whether a tone was played (the ‘Hit’ nose port) or not (the ‘Correct Reject’ nose port) on each trial. Correct choices were rewarded, but only after a variable delay period. This paradigm provided a neat way of assessing perceptual confidence in mice - the longer the mouse waited, the more confidence it had in its choice. In a significant minority of trials, mice reported hearing a tone with high confidence even when no sound was played. Interestingly, the frequency of these high confidence ‘false alarms’ increased when mice were given ketamine, a drug known to induce psychosis-like experiences in humans. Furthermore, when an analogous task was given to human participants, people with a history of psychosis-like experiences reported a greater number of high confidence false alarms compared to control participants. Taken together, these observations suggest these perceptual false alarms rely on at least some of the same circuitry involved in psychosis in humans and could therefore be used as a model of ‘hallucination-like perception’.
Developing this model of hallucination-like perception in mice enabled Katharina to begin exploring the neural basis of hallucination and the influence of dopamine on this circuitry. Using a combination of fibre photometry, optogenetic/pharmacological manipulation, and computational modelling, she found that dopamine fluctuations in the striatum appeared to be encoding expectations about the upcoming stimulus in this task. She also found that artificially increasing dopamine levels in a particular region of the striatum could increase hallucination-like perceptions, a change that was reversed following delivery of the antipsychotic drug haloperidol. This observation suggests that dopamine plays a key role in representing and integrating internal expectations with incoming perceptual information and offers a potential mechanism by which antipsychotic drugs exert their effects. This represents a hugely exciting step towards a biological and neural circuit explanation of the dopamine hypothesis of psychosis.
Looking back, Katharina admits that developing and testing this model was not as straightforward as it now sounds. It was not clear from the outset whether mice would be capable of learning this task, and even when they did it took a long time to train them. Furthermore, when she began to analyse the data, she didn’t immediately find the differences in dopamine across trial conditions that she was expecting. Katharina acknowledges that research inevitably comes with its frustrations and disappointments, but that working with patients constantly reminds her of the big picture and what she’s working towards. “My general strategy is to just concentrate on the big picture … think about a few patients that I can remember and their parents … that always brings me back on track and helps me to just keep going,” she says.
Katharina has recently been appointed as a clinical group leader at the Francis Crick Institute in London. Her position is that of an academic-clinician, meaning she intends to continue working as a psychiatrist while running her lab. The goal of her lab is to use this hallucination-like perception paradigm to delve even deeper into the neural circuits of psychosis. She’s also interested in exploring the contribution of the immune system to psychosis, a link that is only just beginning to emerge. While setting up a lab in the shadow of the pandemic presents its challenges, not to mention the novel responsibility of managing postdocs and supervising students, Katharina is excited and ready to throw herself into the next stage of her academic journey.
Find out more about Katharina and her lab’s research here.
Listen to Caitlin’s full interview with Katharina on March 1, 2022 below!
