Mayfield Lecturer Dr. Andres Lozano looks to DBS for new solutions to depression, Alzheimer’s and epilepsy

Andres Lozano, MD, PhD
Andres Lozano, MD, PhD, the acclaimed neurosurgeon from Toronto, discusses novel surgical approaches to neurological disease during the 2014 Mayfield Neuroscience Symposium.

Andres Lozano, MD, PhD, Professor and Chairman of Neurosurgery at the University of Toronto and the 2014 Mayfield Lecturer, inspired an audience of faculty and neurosurgery residents Friday by illuminating the promise of deep brain stimulation (DBS) surgery for a wide range of conditions, including epilepsy and disorders related to movement, mood and memory.

“There is no difference between neurology and psychiatry,” Dr. Lozano said. “There is no distinction. Signs and symptoms of disease arise as a consequence of dysfunction within brain circuits. This occurs in motor diseases, mood disorders and memory disorders.”

Eliminating or reducing dysfunction by adjusting brain circuits with DBS lies at the heart of Dr. Lozano’s pioneering vision, which has earned him international acclaim. DBS he said, is “the most active area of growth in neurosurgery.”

Dr. Lozano’s lectures were part of the 31st Mayfield Neuroscience Symposium at the University of Cincinnati College of Medicine. The event coincided with graduation ceremonies for three neurosurgery residents: Vincent DiNapoli, MD, PhD, and Lauren Ostling, MD, and Christopher Sanders Taylor, MD. Dr. Lozano was was introduced by Mario Zuccarello, MD, Chairman of the UC Department of Neurosurgery and the Frank H. Mayfield Chair.

Old diseases, new approaches

Dr. Lozano, the RR Tasker Chair in Functional Neurosurgery at University Health Network, has shaken up the field of neurosurgery by forging a new way of thinking about disabling disease. He sees wide, untapped potential for DBS, which involves delivering an electrical current to specific areas of the brain via surgically placed electrodes. “We may be able to change the natural history of some diseases,” he said.

DBS has been used for years to help patients with Parkinson’s disease and essential tremor. The electrical stimulation disrupts neurons that, instead of firing randomly, fire in clusters and cause tremors. “The same principle will apply not only to Parkinson’s disease but also to other disorders, including psychiatric disorders, where small populations of neurons are dysfunctional,” Dr. Lozano said.

He presented a case study of a woman whose severe tremor had been controlled for 18 years by DBS. When the stimulator was turned off, however, the severe tremor returned. “Over 18 years her stimulator has delivered 1 billion punches,” he observed. “And yet the tremor comes back immediately when the stimulation is turned off. Even after a billion stimuli, the cells keep their bad habits.”

A DBS therapy for epilepsy, recently approved by the FDA, involves placing electrodes in the thalamus. A recording device on the skull picks up an electrophysiologic warning before a seizure, providing a 5-second window in which to stimulate and deliver a pre-emptive strike. “Rather than stimulate continuously, we can wait until we detect an important event and then have the stimulator kick in when that occurs,” Dr. Lozano said. “This concept in fact has already started. I suspect that if insurance companies pay for it, we will have a new therapy for seizures.”

Researchers at the University of Toronto are also studying DBS for severe depression, targeting an area of the brain, the subcallosal cortex, that is involved in thoughts that are disturbing or sad. In patients with severe depression, this area is on overdrive. Research findings thus far are inconclusive, Dr. Lozano said, and whether this concept will move forward is unclear.

But DBS of the subcallosal cortex in patients with anorexia has shown great promise. When that target was used to treat 16 patients who had suffered from anorexia for a median of 18 years, one half had returned to normal weight a year later. “We think we are treating depression and obsessive compulsive disorder in this situation,” Dr. Lozano said. “They’re less depressed, less anxious, and they were able to enter a treatment program for eating disorders and gain weight. We think it’s an indirect back door to treating anorexia.”

From the darkness of Alzheimer’s, discovery

If that doesn’t put you on the edge of your seat, this will. Dr. Lozano is already imagining a day when surgeons might use DBS to improve cognitive function. The idea holds profound ramifications for an increasingly prevalent disease – Alzheimer’s – that is the most common cause of dementia in people age 65 and older and that already afflicts an estimated 5.3 million Americans.

In a Phase 1 trial of DBS of memory circuits in Alzheimer’s disease, Dr. Lozano and his team targeted an area adjacent to the fornix, a structure that holds 1.2 million axons and that Dr. Lozano believes is a marker in the memory circuit. The fornix transports signals from the hippocampus, which helps consolidate memories, to the hypothalamus, which controls hunger, thirst, fatigue and metabolic processes. (Because the fornix cannot be safely touched surgically, Dr. Lozano’s team stimulated the adjacent area with voltage that was high enough to spread to the fornix.) In 30 percent of patients who had mild to moderate Alzheimer’s disease, stimulation of this area with 7 volts resulted in vivid, autobiographical memories.

Dr. Lozano and his team subsequently investigated whether DBS could alter glucose utilization in the brain, which drops in patients with Alzheimer’s and appears in brain scans as areas where “the lights are out.”

“The question is, ‘Are the lights out forever, or can you turn them back on?’” Dr. Lozano asked. “We measured glucose utilization before surgery in patients with Alzheimer’s and then again a year later to see what had happened to glucose utilization in the brain. And sure enough, these areas showed an increase in glucose utilization a year later. That means that this is partially reversible [in milder cases of Alzheimer’s]. The lights are out, but there is somebody home and it is possible to at least partially turn the lights back on. This is important, because if these areas now are able to use glucose again, it means their functions may return. It would be really exciting if there was a reversible component to Alzheimer’s disease.”

Dr. Lozano and his colleagues have just finished enrolling 42 patients with mild Alzheimer’s in a study involving the implantation of electrodes to stimulate the fornix. One half will receive DBS immediately, while the other half will receive stimulation after a delay of one year. “We will have to wait a year to see what happens,” Dr. Lozano said.

Dr. Lozano and his team discovered the potential of the fornix as a memory target by chance. While investigating whether DBS of the hypothalamus could reduce hunger in a morbidly obese patient, they found that simulation near the fornix generated vivid memories (in black and white at 5 volts and in color at 7 volts). The device did not alleviate the patient’s appetite, but his ability to remember lists of words soared. “We knew that neuro-anatomic circuits mediating memory are accessible,” Dr. Lozano said. “We now knew that the function of memory circuits could be modulated and that this could have therapeutic implications for patients with memory disorders.”

The story of the obese patient made international news, leading Dr. Lozano to a few rarefied moments of glory in the public eye. The concept of capturing lost memories with DBS was featured in a French comic book and in an episode of the TV drama House. “You know you’ve made it when House has you on it,” he said.

Dr. Lozano noted, however, that the doctors’ ability in House to extract a specific memory via DBS was more fiction than fact.


— Cindy Starr