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
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.