The Sad Place

Two decades ago, Professor Tatia Mei-chun Lee, Chair Professor of Psychological Science and Clinical Psychology and May Professor in Neuropsychology, was puzzled by a patient’s symptoms. The man had suffered from acute liver failure and undergone an emergency liver transplant. Several months later, he began to experience pathological crying – he would cry over situations that previously never phased him and he could not control the crying. Findings of an MRI scan of his brain identified lesions in an area of the brain about which hitherto little had been written: the pons.

The pons is located at the bottom of the brain, in the brainstem. Until about a decade ago, most fMRI brain research looked at the cortical rather than the brainstem regions because of a resolution trade-off, and also a common assumption that the upper brain areas were where cognitive functioning took place.

However, as technology has caught up, it has enabled Professor Lee to investigate the pons more thoroughly. Since 2015, she has published several studies about the pons, including a recent one showing its role in depression. The findings are an important contribution to public health.

“Mood disorders and stress-related disorders are a significant health threat, as identified by the World Health Organization. The more knowledge we have about the mechanisms involved, the better we will be able to understand how we can manage these disorders,” Professor Lee said.

Eliciting responses

Her first groundbreaking study in 2015, in which she worked with Peking University, used a 3 Tesla scanner to conduct fMRIs of people’s brains as they looked at pictures meant to elicit an emotional response, such as a happy baby – called affective stimuli. The resulting brain images substantiated her instinct about that long-ago patient.

“First, we confirmed that when people were looking at affective stimuli, the pons did activate. And second, we identified a structural connection between the pons and the corticolimbic area, particularly the hippocampus, which was associated with affective regulation,” she said.

With that connection identified, they began a second study to see if there were any connections between the pons and the eyes. Other researchers had found such a link in animal studies, as well as impacts on human mood through visual stimulation, such as light therapy. Professor Lee and her colleagues were able to use fMRI to identify a bundle of fibres related to the eye that were connected to the pons region.

Her most recent study, published this year with Professor Lin Chen of the Chinese Academy of Sciences, used a more powerful 7 Tesla fMRI scanner to look more closely at activity in the small structure of the brain, particularly among people who are depressed. A connection was confirmed between the pons and the amygdala, which is involved in processing affectively negative stimuli. But most importantly, only clinically depressed people demonstrated hyperactive amygdala-pons connectivity. Furthermore, this connectivity was shown to be a significant indicator of depression in these patients and the severity of their symptoms.

Dysfunctional connection

“The strength of this connection was positively associated with the severity of depressive symptoms,” Professor Lee said. “We speculate that the pons interacts with the amygdala to perform signal exchanges after receiving affective information. A specific sadness-processing connection between the amygdala and pons appears dysfunctional among people with depression. These findings offer important insight into the potential mechanisms underpinning the manifestation and maintenance of depression.”

Taken together, the findings suggest visual stimulation may be an avenue for further research to identify more precise interventions for depression.

Professor Lee, who was elected a Fellow of the Academy of Social Sciences in the spring, is one of the very few scholars worldwide looking at how the pons interacts with other brain regions to regulate emotion. Her pursuit of this research is part of her overall goal of producing a more complete picture of the affective regulatory system in the brain.

“If we can identify certain activity pathways or connectivity that help mark disease or mood problems and the severity of behavioural problems associated with that, we could then target intervention and look to see if we can revert the marked pathway or neural activities, rather than simply relying on self-reports from the patients,” she said.