Each year in the United States, more than 2 million people are diagnosed with treatment-resistant depression.
In desperation and hopelessness, some brave patients voluntarily agree to surgery to implant experimental "pacemakers" in their brains.
These implanted electrodes are part of a treatment known as deep brain stimulation, which is currently used to treat some cases of Parkinson's disease and epilepsy.
Clinical trials are now beginning to test whether this therapy can also be used to treat severe cases of major depressive disorder.
The first results are promising, although controversial.
In 2021, a patient who received one of these pacemakers reported that her depressive symptoms suddenly disappeared after the surgery.
«"I wasn't sure it would last," she said then. "But it did..."»
Now, neuroscientists at the Icahn School of Medicine at Mount Sinai have used the brains of three monkeys to show how the therapy can have such long-lasting effects.
This appears to result in rewiring of key brain regions involved in the development of depression.
«"The most exciting thing about our results is that they change our understanding of deep brain stimulation," says neuroscientist Peter Rudebeck.
«"For the first time, we've shown that deep brain stimulation doesn't just change the brain's electrical activity in the short term; it can actually rewire the structure of white matter, essentially rewiring the brain circuits associated with depression.".
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It's not yet known whether deep brain stimulation can induce similar white matter changes in the human brain. However, these signs in a close relative of primates are quite revealing.
The white matter of the brain contains nerve fibers, the "extensions" of neurons, which are protected by a fatty sheath called myelin. This protective layer helps transmit electrical signals between brain cells more quickly and efficiently.
Patients with depression typically experience white matter degradation in the brain.
While it is still unclear whether this relationship between depression and white matter is related to behavioral symptoms, the link has been consistently confirmed in numerous studies.
Researchers at Mount Sinai Medical Center have found that deep brain stimulation in monkeys increases myelination of brain cells in areas involved in mood regulation.
Illustration of myelinated nerve fibers. (Photobank Science Photo Library/Canva)
As the authors write in their published paper, the therapy also changes the way neurons communicate in various other brain networks, «most notably the default mode network, which is thought to be associated with depression.».
Overactivity of the brain's default mode network is associated with depression.
«Overall,» the research team concludes, “our data suggest that white matter remodeling, as well as selective changes in multiple neural networks in the brain, may contribute to the therapeutic efficacy of deep brain stimulation.”.
No one yet knows why depression occurs or why its symptoms vary so greatly from person to person, although some risk factors are known.
Many standard treatments for depression are based on hypotheses about the causes of this mental disorder, such as a lack of serotonin in the brain.
However, for a third of patients with major depressive disorder, standard treatments such as antidepressants or psychotherapy appear ineffective.
Until recently, electroconvulsive therapy was one of the few available alternatives.
This treatment method involves electrical stimulation of the brain to induce controlled seizures under anesthesia and appears to be very effective in treating episodes of mental illness. However, it is not necessarily a long-term solution.
Additionally, this method comes with risks and negative side effects, such as nausea, headache, fatigue, confusion, and temporary memory loss, and is not suitable for everyone.
This is why some researchers are turning to deep brain stimulation.
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A brain implant that works like a neurophysiological "pacemaker" could become a more precise alternative to electroconvulsive therapy.
Once implanted in the brain, the device delivers high-frequency electrical impulses, but the patient usually feels no stimulation.
For epilepsy or Parkinson's disease, deep brain stimulation targets the gray matter, or cell bodies of neurons, in the parts of the brain responsible for movement control.
However, in the case of depression, the best results in clinical trials to date have typically been achieved with implanted devices that act on the white matter of the brain.
One potential target may be white matter tracts adjacent to the subcallosal anterior cingulate cortex, a region involved in mood regulation.
«"It was previously unclear how deep brain stimulation affects its structure and function," explains neurologist Helen Mayberg.
But research on monkeys is changing that.
«This study fills a significant gap in our understanding and points to an underappreciated mechanism that promotes sustained long-term recovery,» adds Mayberg, “something we have observed in our long-term clinical studies of depression using deep brain stimulation.”.
See also: Common arthritis drug appears to help where antidepressants fail.
Researchers at Mount Sinai Hospital are among the first in the US to test how deep brain stimulation can help treat depression.
In further studies on monkeys, they are delving deeper into the causes of these symptoms in the brain.
«"Now that we know that deep brain stimulation can stimulate white matter structural plasticity, we can start thinking about how to optimize stimulation approaches and perhaps develop new treatments that target these mechanisms non-surgically," says Mayberg.
The results of the study were published in in the journal Nature Neuroscience .
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