Despite recent scientific breakthroughs that have vastly improved our understanding of some drivers of disease, there’s one part of the body that remains shrouded in mystery – the human brain.

This is due, in part, to the unparalleled complexity of the brain—a 3-pound organ with billions of nerve cells and fibers connected by trillions of synapses—as well as the difficulty in observing brain processes in living humans.

These unknowns make it challenging to identify changes that occur in the brains of individuals with disorders such as depression, bipolar disorder and schizophrenia. If we’re still not sure how a healthy brain works, how can we figure out what goes wrong in disease?

Mass General researcher Jacob Hooker, PhD, is working to answer some of these questions using an imaging technique called positive emission tomography (PET).

How Better Brain Imaging Could Help

Hooker, an investigator at the Martinos Center for Biomedical Imaging and Phyllis and Jerome Lyle Rapport MGH Research Scholar 2016-2021, has identified three key ways that better imaging could improve the diagnosis and treatment of brain disorders.

The first is by providing researchers with a better understanding of how drugs that are successful in treating disorders such as depression work on a functional level.

For example, selective serotonin reuptake inhibitors such as Sertraline and Paroxetine increase serotonin levels in the brain within a day or two, but most patients don’t feel any benefits for several weeks. Lithium, a mood stabilizer, similarly has a mysterious mechanism that researchers are only recently beginning to understand. 

Researchers also need a better understanding of why promising new treatments fail when they get into clinical trials. Treatments for disorders of the brain and central nervous system have an extremely high failure rate. Understanding what led to the failure could help in developing more effective treatments.  

Better brain imaging will also help to identify signature changes in brain activity that will enable precise diagnosis of patients with schizophrenia, bipolar disorder and major depressive disorder. “Our classification of brain disease is very historic and symptom-driven and there are a lot of blurry lines, especially when it comes to mental illnesses,” Hooker says.

Better brain imaging will also help to identify signature changes in brain activity that will enable precise diagnosis of patients with schizophrenia, bipolar disorder and major depressive disorder. “Our classification of brain disease is very historic and symptom-driven and there are a lot of blurry lines, especially when it comes to mental illnesses,” Hooker says.

PET Imaging in Action

PET imaging is a technique in which individuals are injected with a short-lived radioactive tracer that has been designed bind to protein or cellular targets of interest in the body. By measuring where and at what rates these tagged molecules connect with their targets, researchers can gain valuable insights into how mental disorders affect the structure and function of the brain and other internal organs.

In a recent study of 14 individuals with schizophrenia and 17 healthy volunteers, a team led by Hooker used PET imaging to show that schizophrenia patients had lower levels of an enzyme called HDAC in a brain area important for working memory, planning and flexibility compared to the healthy volunteers. The patients with the lowest levels of HDAC also scored lowest on cognitive tests that were administered as part of the study.

Since HDAC has previously been shown to modify gene activity in the brain, the results suggest that there could be a connection between HDAC levels and the onset and progression of schizophrenia.

Aberrant levels of HDAC had previously been observed by researchers from Hooker’s lab and others in postmortem samples of schizophrenia patients, this study was the first to show the same reductions in living patients.

The Long Road Ahead

While Hooker is pleased with the findings, he knows there is much work ahead to understand how changes in HDAC levels impact genetic, cellular and metabolic processes in the brain and to determine if modifying these levels could be an effective treatment strategy. It could take two or three decades to get the full picture.

The unrestricted funding provided by the MGH Research Scholars program ($100,000 per year for five years) has been key to sustaining momentum for long-term research projects such as this that go beyond the typical 5-year timeframe of federal research grants.

“It’s exciting to find a signal that separates patients and healthy controls, but until we can understand the implications of this difference, we don’t know if it is good or bad,” he says. “Ten years ago, if you asked me how excited I would be to get this kind of data out, I would think of it as an amazing finding. Now it’s more of an amazing stepping stone.”

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