Past

I was a precocious child. Always anxious to do things that mattered, that were different, that met challenges.

In college I thought I wanted to be a molecular biologist – because genes mattered.

But I was not gifted at the lab bench.

Although I enjoyed learning about Francois Jacob and Jacques Monod, and their rebellious adventures in and out of the lab, Molecular Biology did not capture me.

I was living in a college dorm, surrounded by social scientists. They would stay up deep into the night having conversations about expansive topics like death and time.

‘How might I, a scientist, have something to contribute?’, I wondered.

One dorm-mate suggested I read Oliver Sacks. I did. I was enraptured. I loved how he weaved the personal narratives of his cases in with extremely creative thinking about the challenges they were experiencing. This book provided a pathway from biology to the social sciences.

It started me wondering about delusions and how to explain them, in a manner that was intellectually satisfying, but that honored their deeply personal presentation. So began a quest to collect as many phenomenological descriptions of what it is like to experience symptoms of mental illness as I could find. Between lectures I would sit in the Psychopathology Library and pore over texts on obscure neurological cases and psychiatric symptoms.

There is, of course, no substitute for talking to people about their experiences. I am very lucky that I got to do that in graduate school, and I continue to be able to today.

My final year undergraduate project involved manipulating dopamine levels in the striatum of rats after a training session where they learned that a light predicted food rewards. Increasing dopamine levels made them learn that association more strongly, even if that learning caused behaviors that led the rewards to be withheld. It struck me, given what I was learning about schizophrenia (that it too was associated with excess dopamine), that this might explain why delusions were so strongly held.

During that time, I went to a departmental talk about dopamine and learning signals by Wolfram Schultz.

With Tony Dickinson, and Pascal Waelti, Wolfram Schultz demonstrated that the dopamine signal in the midbrain appeared to embody a particular learning mechanism, hitherto only inferred from behavioral experiments. This quantity was prediction error; the mismatch between what you expect and what you experience, which can provide an impetus to new learning.

I wondered what would happen if prediction errors were signaled when they shouldn’t be. Might that drive learning, attention, and inference, toward things that ought to be discounted and ignored? Might it be the reason that delusions form? How might that inform how delusions are maintained? I have been trying to answer those questions ever since. I have been extremely lucky to have found a mentor in Paul Fletcher, who continues to inspire and guide me, with the clarity and creativity of his thinking and his careful and compassionate clinical ear.

Paul and I set out to test the prediction error hypothesis in humans using functional neuroimaging, drug models, and patient studies. We found a brain signal for prediction error during belief updating. We found that patients with first episode psychosis did indeed evince aberrant prediction errors which correlated with the severity of their delusions, and that acute ketamine induced psychosis and aberrant prediction errors.

Building a Lab

At Yale, I have been fortunate to be able to continue that work with John Krystal, and to complete a revolution of translation; from ideas inspired by animal studies, through patient work, and now back into animals, under the mentorship of Jane Taylor. I have also been fortunate to learn from and work with Ralph Hoffman (now sadly deceased) and Al Powers, extending the conditioning account to hallucinations with some success.

This work has contributed to the development of predictive coding theory – the idea that the brain and mind work by making predictions and minimizing prediction errors. We have applied it to explain a variety of symptoms of mental illness. We have shown that people form delusions under the influence of an errant learning signal in their brains, that drives them to attend to and learn about merely coincident stimuli, thoughts, and percepts, and imbue them with delusional meaning and significance. More recently this has expanded into the predictive coding account of psychosis, which seeks to explain hallucinations too, not solely in terms of prediction errors but also errant perceptual predictions.

We are trying to make this work practically useful in the clinic– relating the brain signals and behaviors to treatment effects (both current and novel, for example Julia Sheffield is testing whether volatility beliefs and prediction errors change with a CBT intervention that targets worry, with promising initial results), and, more broadly, trying to render psychotic symptoms more relatable and understandable by studying them alongside psychosis-like phenomena in the general population.

Founding Tetricus & Personily

I am very proud of the practical, clinical, experiments we are doing in the lab.

But they aren’t happening quickly enough.

Funding cycles are long and even with a dense network of collaborators we aren’t able to complete the studies quickly enough on big enough samples of people.

I co-founded Tetricus (Personily’s parent company) to bring insights from my lab to the clinic – to help patients in need — more quickly

Leveraging tools from the tech industry, and the power of big data, combined with the insights into brain and behavior from my lab and beyond, we are learning how profiles of patients differ, so we can ultimately move psychiatry towards providing more nuanced diagnoses and treatment recommendations, and increase awareness and understanding of people’s challenges and strengths when it comes to mental health.

When I tell people about my work in the lab, it seems to resonate – to help them understand themselves differently. This is why Lindsay, Lois and I created Personily; to share the cutting-edge science of mental health and brain function directly with individuals that can use it in their own lives, immediately. This is, indeed, the shortest “bench to bedside” cycle one can achieve.