It sounds like B-grade science fiction. You bury an electrode deep in someone’s brain, and set it to pulse a hundred times every second; or, from the outside, you pump a pinpoint flow of magnetic current through the skull. But brain stimulation—the various methods of zapping electric current into the brain—is being used today to treat diseases like Parkinson’s, obsessive-compulsive disorder, and depression.
“It really astounds me every time I implant a patient with a deep brain stimulator,” says Michael Fox, a neuroscientist at Harvard Medical School. “You can see this enormous therapeutic benefit, but as a scientist you’re absolutely struck by how little we know about what it actually does to the brain.”
Although it’s been used in medicine for over 15 years, modern neuroscience still can’t explain what zapping the brain with electricity actually does, and why doing it can help fight disease. But today, a team of neuroscientists lead by Fox has put forth the first unifying theory. In a paper published in this week’s edition of the science journal Proceedings of the National Academy of Sciences, Fox has provided proof that all brain stimulation techniques work by hacking into discrete circuits of brain cells—and that for specific diseases, like depression, all stimulation treatments (that work) tap into the very same circuit.
Fox’s research team came to this conclusion by overlaying a newly developed map of the human brain’s connectome—the rough circuit diagram of how groups of neurons are connected with one another—onto a massive trove of clinical data detailing where effective brain situation treatments were focused for 14 different diseases. All the treatments—which were for diseases as varied as Parkinson’s, Tourette’s, epilepsy, and anorexia—fit into the circuit-theory. “This shows that if you want to understand the mechanics of brain stimulation, you have to think about a network effect,” Fox says.
If you want to understand the mechanics of brain stimulation, you have to think about a network effect.
“In some sense, this is not a new concept. It’s a truism now that many neurological brain disorders are, in essence, circuit disorders,” says Helen Mayburg, a neurologist at Emory University who specializes in brain stimulation and was not involved in the research. But, Mayburg adds, Fox’s team is the first to give brain-wide proof that these neural circuits underlie brain stimulation. “And to this end, the paper is really quite brilliant in its synthesis. He’s effectively leveraged the new connectome data from projects like the Human Connectome Project,” she says.
Two DBS leads enter a brain. Image: Hellerhoff/Wikimedia
Nader Pouratian, a UCLA neurosurgeon who also was not involved in the research, agrees with Mayburg that Fox’s theoretical framework will help pave the way for a new era of experimentation—allowing scientists not only to develop more effective clinical treatments, but to break down the mystery of what stimulation actually does to the brain’s individual circuits, and how that varies from circuit to circuit, or disease to disease. “[This] also helps the clinical and basic-science worlds of brain stimulation research converge. Right now there’s surprisingly great divide, but closing that will seriously accelerate our understanding in both spheres,” Pouratian adds.
In fact, one experiment using a circuit-directed approach to brain stimulation has already been published. A month ago a team at Northwestern University lead by Joel Voss published the results of an experiment in the journal Science that used these very principles to actually improve memory in healthy subjects. This was done using a non-invasive brain stimulation technique, called TMS, to zap a neural circuit found to be connected to the hippocampus, a deep-brain structure involved with memory. For the researchers this finding was doubly exciting, because without co-opting neural circuits, the hippocampus is completely out-of-reach, except for techniques that require brain surgery.
Voss explains that, taken together, both his experiment and Fox’s new paper hint at the promise that we may eventually be able to develop non-invasive clinical treatments that mimic the effects of those that currently require brain surgery, like deep-brain stimulation. “Brain surgery is associated with a lot of complications, including death, and even in the most needful circumstances is questionable,” Voss says. Although he emphasizes that there’s still a lot of work to be done, “if you’re using a technique that’s modulating an entire neural [circuit], in many cases it may not matter where you start,” Voss says.
The larger idea is that networks of neurons that wire together, also fire together.
Fox’s new theory still leaves the biggest question unanswered: What does the electrical jolt of brain stimulation physically do to brain cells or neural circuits?
Lynn Rogers, a neuroscientist Northwestern University who co-authored Voss’s Science paper, explains that the question is excruciatingly complicated, but one prevailing theory is that, “certain types of stimulation make neurons more likely or less likely to fire," she says. "And the larger idea is that networks of neurons that wire together, also fire together." Rogers adds, however, that scientists are unsure if this is true across all neural circuits, or just some, and notes that we haven’t yet pinpointed the physiological reason why the stimulation effect moves across these neural circuits.
But Fox and others are quite excited that his research team’s paper serves up more questions than it does answers. “What comes next that’s the most exciting part,” Fox says. “All we’ve done is set up a testable framework. How future experiments based off this framework advance our understanding or improve clinical care remains to be seen.”