Alik Widge, MD, PhD and Husam Katnani, PhD, consult in the lab.
Alik Widge, MD, PhD and Husam Katnani, PhD, consult in the lab.

Most of us learn at an early age that the shortest distance between two points is a straight line.

But when it comes to treating disorders of the mind with deep brain stimulation (DBS), the quickest path to progress may be the indirect route.

That’s the thinking of Massachusetts General Hospital researchers Husam Katnani, PhD, and Alik Widge, MD, PhD, who are working to develop a new approach to DBS that better mirrors the way communication takes place in the brain—namely as a series of interconnected circuits, loops and waves.

This strategy could lead to much-needed breakthroughs in treatments for patients with traumatic brain injuries and major depressive disorder, among others.

ABOUT DEEP BRAIN STIMULATION

Deep brain stimulation (DBS) is a process in which a battery-powered wire with multiple electrical contacts, called a lead, is surgically implanted into the brain. This lead is then used to modulate the transmission of electrical brain signals.

DBS is an effective therapy for patients with Parkinson’s disease and other tremor disorders. In these patients, the high-frequency electrical signal transmitted by the lead helps to modulate the abnormal neural firing that causes the motor disorder.

For the past two decades, Mass General researchers have been working to expand the use of DBS to also help patients suffering from mental health and cognitive disorders. Thus far, these efforts have met with limited success.

In one of the largest clinical trials to date using DBS for treatment-resistant depression, for example, participants who received DBS did not improve at a rate better than placebo.

Katnani and Widge believe those early setbacks were part of a crucial discovery that now points to a better way. Rather than attempting to treat these conditions with a single constant electrical signal, like as done with Parkinson’s disease, they are taking a more nuanced approach.

“What we’re working on is something far more elegant,” Katnani explains. “Let’s look at multiple nuclei in the brain, lets record at multiple nuclei in the brain, and let’s treat at multiple nuclei in the brain in a more coordinated and dynamic fashion. That way we emulate the natural neurophysiology and bring back the real function that exists.

TRAUMATIC BRAIN INJURY

Katnani, an instructor in neurosurgery, is exploring the use of targeting multiple regions in the brain and activating each region in a coordinated fashion and only at appropriate time points in order to help patients recover from deficits caused by traumatic brain injuries (TBIs).

While TBIs differ in how they damage the brain based on the force and location of the impact, many TBI patients experience common difficulties with concentration, learning, memory, and motivation, Katnani explained. These conditions often have a significant burden on the families of TBI patients and the community.

Researchers have pretty good idea of the location in the brain where learning and memory skills are built. By identifying circuits in that area that are still functioning and stimulating them with current, Katnani hopes to boost the learning, memory and skills of TBI patients to facilitate a faster rehabilitation.

Rather than trying to reactivate circuits that have been damaged beyond repair, Katnani’s strategy is to boost existing circuits so they can optimize existing circuitry to perform better than average. The hope is that this will bring the patient’s overall functioning closer to baseline. “If we can augment circuitry that’s still functional, then that circuit can work to rectify the brain itself.”

So far, the process has been shown to improve those skills in animal models of brain injury. And, in experiments conducted with consenting human participants in the Epilepsy Monitoring Unit (EMU)—who have similar DBS-like wires implanted to monitor seizures—Katnani has demonstrated that stimulation to those circuits can improve learning and skill development in humans as well.

MAJOR DEPRESSIVE DISORDER

Widge, a physician-researcher in the Department of Psychiatry, is taking a similarly nuanced approach to treating major depressive disorder (MDD) and post-traumatic stress disorder through deep brain stimulation.

According to Widge, untreatable mental illness represents the most costly set of medical conditions in the country and is the leading worldwide cause of disability.

“We’ve had tons of innovation, billions of dollars of new drugs, new psychotherapies, but the actual mortality of mental illness has not changed. In fact, the second the patient gets off the drug or stops therapy, they so often relapse. And that’s fundamentally because we’re not changing the underlying cause.”

“The issue is that mental disorders aren’t strokes; they aren’t TBIs; they aren’t a single place in the brain that you can see on an MRI. They are disorders of information flow and distributed circuits.”

Widge’s current research seeks to help MDD patients better control their moods by strengthening the signal loop between the prefrontal cortex and the amygdala. “This circuit comes up in basically every mood and anxiety disorder out there.”

This approach is different from the previous studies that failed to improve on placebo because they are focusing on the interaction between two parts of the brain, rather than just trying to activate one area. “When two structures have rhythms that are out of sync, communication breaks down. If I am talking and you’re not listening, no information gets transmitted. When they are in sync, and when they are reliability oscillating in tune with each other, they’re on the same wavelength.”

A COMMON CONNECTION

Both Widge and Katnani trained in their respective fields at the same time and in the same city (Pittsburgh), but they didn’t meet until coming to Mass General.

Their common point of contact, like so many interested in deep brain stimulation at Mass General, is neurosurgeon Emad Eskandar, MD, PhD

“Dr. Eskandar is highly sought after as a collaborator for people like us who are interested in the brain and interfacing with it,” Katnani says. “He brings people together.”

Through Eskandar, Katnani and Widge have been able to work directly with patients in the EMU and with patients who have DBS devices implanted, which has proven to be invaluable in expanding the scope of their collective research. So too has been the hospital’s forward-thinking approach to expanding the use of DBS beyond treatment for Parkinson’s disease and tremor disorders.

“At Mass General specifically, one of the things we’ve done is position ourselves as a center of excellence of neuromodulation outside the classic movement disorders,” Widge says.

“You could argue that there is some place in the world that is better than MGH at any one thing, but nobody else can match the collective of what we can do.”

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