By Nick Statt

Some people suffer from depression so severe that therapy, medication and even standard brain surgery cannot help their condition. But a recent joint study between Brookhaven National Laboratory and Cold Spring Harbor Laboratory scientists has found a substantial link between certain brain cells and depression, furthering research in the field and paving the way for potentially revolutionary treatments in the future.

The key lies in the lateral habenula, a tiny structure of neurons within the brain. When it happens to be hyperactive, or in other words enhanced and operating at a higher level than usual, it contributes to higher levels of depression.

“Because we know this habenula neuron will send projections to the dopamine neuron, it will have a strong influence on depression,” said Dr. Bo Li, a Cold Spring Harbor Lab researcher and co-author of the article alongside Dr. Fritz Henn of Brookhaven and Roberto Malinow of the University of California San Diego School of Medicine, among others. Li is referring to the brain’s reward system, which fuels our dopamine levels and is substantially crippled by the hyperactivity of the lateral habenula.

The principle method of the study involved observing two kinds of specially bred rats – ones with “learned helplessness,” a universal type of depression that bridges both animals and humans, and ones without that acted as the control of the experiment. Fritz Henn, a neurobiologist and psychiatrist, bred the rats to create this scenario and to study its effects on the habenula.

“The region that came out most significant in the study was the habenula,” said Dr. Martine Marrione, a researcher at both BNL and CSHL, as well as a co-author of the study. “It was the helpless animal, the ones with the depressive-like phenotype, that showed the habenula activity.”

So Henn, Li and the other researchers turned to deep brain simulation, a modern, yet extremely dangerous, treatment that involves placing an electrode in the brain. Their aim was to see if they could reverse the helpless behavior by electrically stimulating the hyperactive habenula. The result was a success.

The study is groundbreaking because it is a culmination of years of other researchers’ foundational work that finally establishes and highlights the habenula as having a pivotal link with depression. Marrione stressed that the study would have been impossible without that foundation.

“All of these researchers that came before us helped drive our interest in studying the habenula and particularly in this animal model that we have with depression,” she said. Previous studies included ones in 1999 that first highlighted the potential importance of the habenula and then one in 2003 that observed the same learned helplessness animal strain as Henn would later do, but did not make the leap of studying the connection between it and the habenula.

As for implementing this treatment in human beings, only one such trial has been conducted. It was on a patient in Germany who suffered from long-standing, treatment-resistant depression. “They thought she would be a good candidate and she agreed, and in this single case there was a positive effect on a human,” said Marrione.

For the unfortunate individuals that suffer from such severe depression, deep brain stimulation is a last resort, and neurobiologists are very aware of this during their research and the subsequent implementing of treatments.

“There’s really a discussion about the ethics related to such a technique,” said Dr. Daniela Schulz, a Brookhaven researcher and co-author of the study. “Obviously one has to be aware of the potential impacts of sticking an electrode into somebody’s brain. Even if it works, the consequences of it, including long-term effects, are not known.”

“We have to ask what are the consequences, the impact. You have to weigh this against potential cures and treatment possibilities,” she added. “There are new chemicals and drugs…it’s just that they don’t work for everyone. We are always looking for new solutions.”

Looking forward, a significant amount of research must still be conducted to fully understand how these depression models are operating in the test animals used by Henn, Li and the others.

“Certainly, we need to do more basic research, trying to understand how these deep brain stimulation method is working in the animal model,” said Marrione.

Li asserts that while they have found a link between the habenula and depression, they still do not understand what can trigger hyperactivity in that region of the brain. That is the plan right now. “We want to figure out the enhancement,” he said.

“If we know that, maybe we can design some drugs to target specifically the habenula neuron that can reverse the enhanced activity,” he added. That would effectively allow depressed patients to avoid the invasive and dangerous deep brain stimulation, and would mark a great breakthrough for clinical depression treatments down the line.


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