Mysteries of neuroscience

What we don’t know: Neuroscience research at CMHC

The third floor of the CMHC houses the Clinical Neuroscience Research Unit (CNRU), an inpatient and outpatient research facility. It’s an honor to be asked to start a dialogue with you about what we do on the CNRU. Over the next few months, I’d like to introduce you to the scientists and clinicians and their teams that work on the CNRU. Today I’d like to introduce you to some of the things we do on the 3rd floor.

Just as others in the building, my CNRU colleagues and I come to work to tackle the problems addressed on the other floors of the CMHC: the debilitating symptoms of mental illness including depression, hallucinations, delusions, drug addiction and anxiety to name a few.

Philip Corlett, PhD. Photo credit: Lucile Bruce

Philip Corlett, PhD. Photo credit: Lucile Bruce

Despite all of the good work that people at CMHC and in the field of psychiatry do on behalf of people with mental illness and addictions, we still face a frustrating lack of understanding of the basis of people’s problems. On the CNRU we are motivated primarily by our desire to improve the lives of patients and their families. We try to understand the roots of patients’ problems by making predictions that we test with experiments. For example, right now in my lab, we’re testing the idea that delusions form when people are surprised by things that they shouldn’t be surprised by. We think we have identified a brain mechanism for that effect and we are developing treatment approaches that target that brain mechanism.

Ideally, our experiments should lead us to a better understanding of mental illness, new and better treatments, and a better quality of life for our patients – goals we share across all the floors of our building.

I call the questions we ask on the CNRU our “known unknowns.” Much scientific research is predicated on known unknowns – gaps in our knowledge that we aim to fill. I would like to point out some of the known unknowns that we focus on and why we focus on them in the CNRU.

We don’t know how the brain makes up the mind

Inside your head is a three-pound universe—a dense network of nerve cells more interconnected than the world-wide-web, with about 86 billion cells. We don’t know how those cells work together to produce your thoughts, emotions, decisions, and your sense of yourself, your mind. This problem is a bit like not knowing the hardware in a computer; the microchips, resistors and circuits that allow it to run programs. Further, we don’t know what the programs that your brain runs are, and we don’t know what problems they are trying to solve. Without this information, we can’t tell whether mental illnesses are problems of hardware (nerve cells), or software (coordinated cell activity) or the specification of tasks to be solved (some combination of hardware and software). Much of the work we do in the Unit tries to answer these questions – how does the brain form beliefs and memories? How do we make decisions? What are the consequences for mental health when these processes go awry?

We don’t know why some people suffer mental illnesses and others don’t

Mental illnesses run in families. That means that there are genetic markers in people’s DNA; the instructions in their cells that guide them to grow and develop, that they inherit from their parents, influence whether they develop the symptoms of mental illness. In the CNRU, scientists are trying to understand what those markers are and use them to design new medications that target more directly the problems that people with mental illness face. This leads me to our next known unknown.

We don’t know why some medications work for some people and not others

There is no one-size-fits-all medication for any of the serious mental illnesses, like schizophrenia, depression, and bipolar illness. Different things work for different people. Take schizophrenia for example. We have known about drugs that block dopamine receptors helping with the hallucinations (seeing or hearing things that other people don’t) and delusions (fixed false beliefs that other people don’t share) for about 50 years. However, between 25% and 50% of patients have residual hallucinations and delusions even when they are given high doses of these standard medications. Presumably these patients suffer their symptoms for some biological reason other than disrupted dopamine. We are looking for those reasons on the unit. When we find them, we will be able to use that understanding to make things better for our patients.

We don’t know why some symptoms persist over somebody’s lifetime

Addiction to drugs like cocaine is a mental illness. It has a chronic relapsing course: even when people manage to quit, they often relapse to drug seeking behaviors and abuse. We don’t know enough about that process. How does the act of drug use reoccur, even after periods of abstinence? Where in the brain are those addiction memories stored? Why do they resurface? What can we do to help? Scientists on the 3rd floor are working on these questions every day.

We don’t know why some people recover and others do not

We believe that people can recover from serious mental illnesses. We don’t know why some do and some don’t. We believe there will be markers in people’s brains, their bodies and their behavior that will predict their prognosis. We will use those measures to guide decision making about people’s treatments, taking a personalized approach to their recovery that will be more effective, efficient and stable.

We don’t know enough about the strengths of patients with mental illness

There is an assumption we make with much of the work that we do on the Unit – that if we understand normal thinking, brain function and behavior, we can make predictions about abnormalities and how they might lead to the symptoms of mental illness. This neglects the range of abilities, passions, and strengths in patients with mental illnesses. We should not ignore the fact that although impaired and debilitated by their illnesses, patients are nevertheless equipped with resilience mechanisms that help them cope with their stigmatizing illnesses. By understanding that resilience, and celebrating strengths, we feel we can better help people cope and recover.

In summary, there is a lot we don’t know. But we are working hard every day on the third floor to address that. Being situated within CMHC allows us to see first-hand the issues that our patients deal with and reminds us how far we have to go.

Serendipitous discoveries

On the other hand, there are unknown unknowns: serendipitous discoveries that fast-forward our work in new and unpredicted directions. In the early years of the new millennium, Dr. John Krystal, our Department Chair was studying the brain glutamate system in patients with depression. Glutamate is a chemical signal in the brain that increases nerve cell activity. Dr. Krystal was studying a drug called ketamine, an anesthetic drug that blocks a certain type of receptor on nerve cells. Unexpectedly and fortuitously he found that people who had been very seriously depressed experienced a short-lived but powerful remission of their depression, some of them for the first time in their adult lives. This happy accident has led to entirely new treatment approach in depression and a focus on new drugs that might alter the glutamate system.

Collaborating for knowledge at CMHC

I want to end with one last known unknown. Here within CMHC, we don’t know each other well enough. I hope you can see from the questions we are asking that we are a creative and dedicated group on the third floor. But we are also realistic and we appreciate that curing mental illness will require a team effort and a multi-faceted approach. We want to get to know you better, whether you are a patient, nurse, physician, mental health worker or custodian. We can all achieve more if we work together. Next time you see me in the elevator, ask me what I am working on that day – I am sure I’ll share enthusiastically and I’ll welcome your feedback. I’d love to hear about what you are working on too. Ultimately, we need to better understand our patients, the challenges they face, and the challenges we all face in trying to assist them. That is our only choice if we are to reduce the number of things we know we don’t know.

– By Philip Corlett, PhD

*Source: Yale University

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