NIMH Director Describes Ways to Better Target Therapy

Research into neural circuits and brain phenotyping may herald new breakthroughs in psychiatry, said National Institute of Mental Health (NIMH) Director Joshua Gordon, M.D., Ph.D., during his presentation at APA’s Spring Highlights Meeting.

“We have made a lot of progress in understanding how different parts of the brain communicate to influence human behavior,” Gordon said. “We have also developed new tools that we can use to manipulate these different brain regions in laboratory models.”

Gordon cited some recent studies done at his NIMH lab using specially designed viruses to target a circuit bridging the hippocampus and prefrontal cortex that is believed to be a key conduit for anxiety-like behaviors. These viruses had special light-sensitive proteins, enabling researchers to turn the circuit on or off using light energy (a research tool known as optogenetics). Using specific wavelengths of light, Gordon’s lab was able to make mice more, or less, afraid of open spaces.

“What that means is we can cure, or cause, anxiety in mice,” Gordon said. Other research groups have also used optogenetics to manipulate behaviors such as binge drinking.

Gordon said studies like these may one day lead to more targeted therapies for mood disorders. He said it’s also possible that technologies such as optogenetics can be adapted to be safe and effective in humans.

In addition to neural circuit research, Gordon highlighted a second long-term research area that NIMH is considering a priority: using computational biology to improve the treatment of heterogenous disorders such as depression.

“You are all aware of the revolution in data science and artificial intelligence that has been changing the way we think about science and society in general,” Gordon said. “We want to take that revolution and harness it for psychiatry.”

Gordon described a technology known as computational phenotyping, which aims to break down depressive symptoms into discrete units and then mathematically define those units. Rather than asking where in the brain happiness is controlled, for example, computational phenotyping asks where in the brain are the different behavioral components that together make up happiness.

He highlighted one study that used brain imaging data of people playing a game of chance on their phones to calculate reward prediction error. Basically, when people are about to decide something involving reward/loss, they have some expectations of how they will react to winning or losing, which guides their decision. Normally the outcomes and expectations match, but in many people with depression, reward prediction is off (rewards are not as pleasurable as thought, which lowers a desire to seek future rewards, for example). This study found that reward prediction in the participants could be localized to two discrete brain regions: the ventral striatum and medial prefrontal cortex.

Other brain imaging studies have found these same two regions show reduced activity in many depressed patients. Gordon noted that linking specific brain regions with specific traits might help with precision medicine efforts. Based on a patient’s symptom profile, physicians might be able to determine which brain regions are affected and then identify the optimal treatment.

That treatment might involve a strategy guided by neural circuit discoveries, which highlights how these two long-term NIMH goals might one day converge. ■