Deep brain stimulation: how far can it go?

Pioneering neurosurgeon Andres Lozano achieved groundbreaking results using a landmark surgical procedure on Parkinson’s and depression. Now he’s trying it on Alzheimer’s by Mark Witten
Andres Lozano

In 2003, neurosurgeon Dr. Andres Lozano was performing an experimental procedure designed to suppress the appetite of a 53-year-old, 420-pound man with a lifelong history of obesity. When Lozano switched on electrodes surgically implanted in the hypothalamus, a brain area that controls hunger, the patient suddenly remembered a visit to a park with his girlfriend 30 years earlier. As the electrical stimulation increased, the details became more vivid, and he could recall colours, sounds, smells and the dress she was wearing.

“It happened by accident and I knew we were onto something important,”  says Lozano, a professor of surgery at the University of Toronto and Canada Research Chair in Neuroscience.

Using a technique known as deep brain stimulation (DBS), Lozano had serendipitously activated the fornix, a bundle of nerve fibres that is the main highway in and out of the brain’s memory circuit. Further tests after surgery revealed the patient’s verbal memory was much sharper when the stimulation was turned on compared to when it was off.  “His ability to remember words went through the roof,”  says Lozano, who decided to perform the identical procedure on six patients with mild Alzheimer’s in a research study. The results from the first small trial of this experimental treatment show promise in reversing the trajectory of an incurable brain disease that affects 500,000 Canadians and five million North Americans.

Deep brain stimulation uses tiny electrodes implanted in specific brain regions to alter abnormal brain activity and repair malfunctioning brain circuits. In Parkinson’s disease, for example, electrodes are placed in areas responsible for body movement to repair the  activity in the brain’s damaged motor circuit. Small electrical pulses from a device similar to a cardiac pacemaker block the abnormal firing of brain cells in Parkinson’s, caused by a lack of the brain chemical dopamine, and replace it with a more regular pattern of signalling that can dramatically reduce motor symptoms such as tremors, stiffness and gait problems. By stimulating a sweet spot, the therapy alters the signalling pattern across millions of interconnected cells in different brain regions throughout the circuit.

“We’re dealing with big problems, devastating diseases where a bold approach is needed”

Today, there is growing excitement about the potential benefits of applying a therapy that has safely reduced symptoms and improved quality of life for over 90,000 people with movement disorders like Parkinson’s. Lozano, who pioneered the use of DBS for Parkinson’s in North America and has treated over 800 patients at the University Health Network’s Toronto Western Hospital, is in the forefront as the first neuroscientist to test and show promising results in targeting the brain’s mood circuit for depression and memory circuit for Alzheimer’s.

He and others in the field are also exploring the use of DBS in trials as a treatment for epilepsy, obsessive compulsive disorder, bipolar disorder, chronic pain, Tourette’s syndrome and severe anorexia.  “A large number of neurological and psychiatric disorders are not well addressed despite our best drug therapies. We’re dealing with big problems, devastating diseases where a bold approach is needed,”  says Lozano, holder of the Dan Family Chair in Neurosurgery at U of T and the RR Tasker Chair in Functional Neurosurgery at UHN.

In a groundbreaking study published in Neuron in 2005, Lozano and neurologist Dr. Helen Mayberg (formerly at U of T and now at Emory University) reported that four of six patients who were considered untreatable showed a striking reduction in depression symptoms six months after starting DBS treatment. Some had previously attempted or considered suicide. Lozano recalls the amazing transformation in one patient during the procedure.  “To our surprise, as soon as we turned on the stimulator the depression went away. Her mood improved, and she became engaged and interactive,”  he says.

By placing electrodes in Broadmann Area 25, a sadness centre in the cerebral cortex, and continuously stimulating it with electricity, the doctors had turned down hyperactivity in the brain’s sadness centre and boosted activity in the frontal lobes, restoring balance to the mood circuit in these severely depressed patients.

In a follow-up study of 20 patients at U of T, UBC and McGill, about two-thirds improved significantly.  “Some of them are working, some are leading a normal life and some went into complete remission. If patients respond to the treatment within three months, they tend to respond over the long term,”  says Lozano, who is now leading a phase 3 trial involving 200 patients at 18 North American medical centres. If proven safe and effective, DBS could be approved by the FDA and Health Canada as an evidence-based therapy for major depression.

After following six Alzheimer’s patients treated with DBS for a year, he observed that the memories of the two with the mildest symptoms got better and two stayed the same rather than getting worse. Imaging showed DBS stimulated brain activity in their memory circuits.  “You can see that areas of the brain, like the temporal and parietal lobes, are lighting up. In Alzheimer’s, these areas are shut down and use less glucose than normal, as if they are affected by a power failure in the circuit. Deep brain stimulation restarts some of the shut down areas and if we restore brain function, we expect patients to improve,”  explains Lozano.

If patients respond to the treatment within three months, they tend to respond over the long term”

Even more remarkably, MRI scans revealed one patient had an eight per cent increase in the hippocampus, the brain’s memory hub, and another had a five per cent increase.  “That’s incredible. In Alzheimer’s, the memory areas of the brain shrink and we’ve never seen the hippocampus grow,”  says Lozano, who then applied DBS to this circuit in rodents and found it increased the growth of new brain cells by two to three times. “The rats that make more neurons get smarter and have a better memory. We wonder whether this could be happening with the two Alzheimer’s patients.”

A phase 2, multi-centre trial is now underway in which 50 Alzheimer’s patients will have electrodes implanted in their brains, but only half will have the stimulation turned on immediately. In the others, it will be turned on in a delayed fashion. This will allow Lozano and his research collaborators to compare and contrast the results in memory performance and brain structure.

“The clock is ticking in patients with Alzheimer’s. We’ve shown in the lab and in a small number of patients that electrical stimulation can change the structure of the brain and grow the hippocampus. We’re upgrading the hardware of the brain and it may mean we could influence the course of the illness,”  he says.

Lozano is expanding the scope of DBS into a vast frontier of formidable diseases for which there have been, until now, few hopes or effective treatments.  “Deep brain stimulation is being tested and used to treat conditions where we’re stuck. We can place electrodes anywhere in the brain. It’s like exploring space. There is so much that’s unknown and so much to discover. That’s where the excitement is,”  he says.

Stimulating a brain to repair itself after stroke

Molly Shoichet

Molly Shoichet of the Department of Chemical Engineering & Applied Chemistry and the Institute of Biomaterials and Biomedical Engineering is finding innovative regenerative medicine strategies to overcome disease in the central nervous system, including traumatic injury to the brain, such as stroke.

Taking advantage of the plasticity in the brain and its resident neural stem cells, Shoichet and her team, in conjunction with Cindi Morshead from U of T’s Department of Surgery and Dale Corbett
from the University of Ottawa’s Faculty of Medicine, are investigating
minimally-invasive techniques to stimulate these particular stem cells to achieve brain repair.“The stroke itself stimulates these cells, but insufficiently to promote repair. By the co-delivery of two growth factors at specified times, we’ve demonstrated enhanced tissue repair,” says Shoichet.
A Band-Aid-like method applied directly to the brain is being tested. By injecting a drug delivery vehicle directly to the brain of animal models, Shoichet has been able to circumvent the blood-brain barrier that prevents most molecules from diffusing into the brain.
“The exciting results from our research pave the way for future studies in larger animal models where rehabilitation and an enriched environment will further promote plasticity in the brain. The ultimate goal for us is to test these innovative strategies in humans,” says Shoichet. —Jennifer Hsu

Better—and cheaper—brain imaging for epilepsy and stroke
Ofer Levi

Ofer Levi

Brain imaging. It calls to mind massive MRI machines or CT scanners, with a patient immobilized while the machine does its work.What if you could go about your daily life while a machine you hardly noticed took images of your brain? It might not be so far off, if Ofer Levi of the Institute of Biomaterials and Biomedical Engineering and the Department of Electrical and Computer Engineering has his way. He’s developing a low-cost, portable optical imaging system to monitor brain dynamics in patients with epilepsy, stroke and traumatic brain injury.

Current techniques, Levi says, “are large systems such as MRI or CT that are the size of a room. You have to be immobile. You can’t leave a patient more than an hour in them.” Optical technologies, on the other hand, offer portable solutions. “You can walk around, and you can be awake,” which gives a much more accurate picture of brain activity. They’re also potentially much less expensive. His team has developed a 40-gram working prototype they’re testing on rats, who carry the equipment around in backpacks. It’s built with the sorts of lasers you find in an optical computer mouse and the cameras found in a cell phone.
Once proven, it’s hoped the technique will allow doctors to monitor the brain dynamics of human patients over a long period of time—on the order of days, rather than the hour or so allowed by current technology. —Jenny Hall

Probing the brain’s recovery mechanisms after traumatic injury
Robin Green

Robin Green

Whether caused by a car crash, a fall or some other incident, traumatic brain injury can be debilitating. Cognitive functions like memory and language are often impaired. So are motor skills such as coordination and balance. Robin Green is trying to better understand how these functions recover. A professor in the Department of Psychiatry, a senior scientist at Toronto Rehab and the Canada Research Chair in Traumatic Brain Injury, Green is examining the idea that there is “competition” between recovery of cognitive and motor functions after traumatic brain injury. In other words, the more one of these areas rec­overs, the less the other one does. This may be because injured
parts of the brain must compete for the limited neural resources
that support recovery following injury. Preliminary findings
support the hypothesis.

A second avenue of research is whether traumatic brain injury is actually a progressive disorder. Green has shown that long after the acute events of brain injury have resolved, grey matter continues to atrophy, white matter integrity is lost and lesions expand. Her lab has found that there is less deterioration when people receive more cognitive stimulation early on. This finding appears to contradict the first. However, if cognitive stimulation (or “environmental enrichment”) is creating new neural resources, then the two sets of findings make sense. Her group is currently embarking on a multi-pronged treatment research study to offset deterioration and enhance clinical outcomes. —Toronto Rehab