Deep Brain Stimulation to Improve the Mind

Andres Lozano

Andres Lozano's interest in how the brain works led him to functional neurosurgery - studying interventions that can improve function. Well defined areas of the brain control sadness, hunger, memory, motor and sensory processing. It is possible to intervene in the circuits involving these centres, using electricity - "the currency of the brain" to turn off or suppress electrical function. For example, it is possible to interrupt the epilepsy circuit, stopping the disorder. Similarly, the discharge of pain neurons or the 10.000 neurons firing four-five times per second synchronously to cause Parkinson's tremor can be interrupted.

Andres studied under Ron Tasker, the world authority on intervention for Parkinson's disease. Following on the success of deep brain stimulation (DBS) in Parkinson's disease, depression has become the next frontier. Area 25 is the sadness centre. When it is in overdrive, evidenced by uptake of radioactive water on a PET scan, the patient is depressed. DBS turns this area down, improving mood. Of 45 patients studied so far, 2/3 were improved.

Tom Insell, who as director of the National Institute of Mental Health enjoys an unparalleled view of the discipline, says "People often ask me about the significance of small first studies like this. I usually tell them: "Don't bother. We don't know enough." But this is different. Here we know enough to say this is something significant. I really do believe this is the beginning of a new way of understanding depression."

The study has now moved on to phase III, with 200 patients to be enrolled. All are patients who have failed to improve on drug or electroconvulsive therapy. The study will be carried out in 18 centers throughout North America. The design includes insertion of the electrodes in all patients. Half will be turned on immediately and half will be delayed for six months.

There have been over 80,000 patients treated by DBS for Parkinson's disease. Every major neurological centre can carry it out, so it would be easy to adapt their systems to intervene in area 25. Unlike the relatively rare diseases treated by neurosurgeons in the past, such as subarachnoid hemorrhage or brain tumours, depression is a common disease. 9% of females and 6% of males are depressed. Of this number, 10-15% are treatment resistant.

These studies led Andres and his colleagues to feel that they are "like space explorers, entering uncharted areas of the brain. Interestingly, there is the same number of neurons in the brain as there are stars in our galaxy. The human brain is the greatest mystery on earth."

Andres has 100% congruence between his clinical and laboratory interests. In his very active lab, PhD students are studying the effects of DBS at the cellular and molecular level. Since there are known appetite centers in the hypothalamus that have been surgically ablated to destroy hunger, he was asked to try electrical stimulation in treatment resistant morbidly obese patients. During DBS, an obese 53 year old man was asked: "Are you hungry?" An electrode had been advanced into his brain to identify a target where stimulation has an effect in suppressing appetite. However, he experienced a "deja vue" sensation. He said: "I feel like I am 25 years old. I am with my girlfriend, hearing the sounds I heard 33 years ago". Now, 3 or 4 months later, the same patient has had a dramatic improvement in his verbal memory. This serendipitous finding precipitated an attempt to improve the memory of 6 Alzheimer's disease patients - by stimulating the memory circuit. In this Phase 1 study, the PhD project of neurosurgery resident Adrian Laxton, there was some improvement of memory and it was clear that the intervention could be done safely. The study is now moving on to Phase II. Neurosurgery resident and PhD candidate Scellig Stone has extended these observations and has shown in the laboratory that this stimulation creates more neurons in the hippocampus in animals. The mice become smarter i.e. better at running mazes. Despite years of study, it appears that the characteristic amyloid deposits in Alzheimer's disease (AD) patients' brains are not the entire story. So far clearance of amyloid doesn't improve memory in AD patients and normal people can have amyloid without impairment. In Parkinson's disease there is no

increase in cells (neurogenesis) by deep brain electro stimulation, but the performance of the circuit is improved. There are apparently areas of the brain that are shut down, but can be recovered as evidenced by reestablishment of glucose utilization in the silent areas. "The lights are out, but someone's at home". In Parkinson's disease, there is no increase in neurons. New neurons are generally not generated except in the olfactory system and in the hippocampus.

"The biggest advances in science are made by questioning dogma. The fundamental belief of science is that facts change. Neurosurgeons have access to the human brain, they are uniquely privileged to be able to study and improve its function."

Decreased metabolism in AD compared to controls

One month of DBS compared to baseline

One year of DBS compared to baseline

Positron emission tomography scans of 6 patients with Alzheimers disease showing areas of decreased glucose utilization before surgery in blue which are reversed with DBS after 1 month or 12 months of DBS. Restoring glucose utilization suggests that these brain areas that were shut down are once again active.

Q: What is your typical day like?

A: "I operate in 2 week blocks, alternating with Dr. Mojgan Hodaie - two weeks in the lab, followed by two weeks of clinical responsibility. There are 3 days of operating in each clinical week. I write and do experiments during the laboratory week. This works out well 90% of the time. I write everyday and everywhere, but finish papers in uninterrupted time." Dr. Hodaie, who was his resident and fellow, is now his colleague with her own very active research program.

Q: What is Neuroethics?

A: This work introduces a new set of ethical challenges, for example: 1. The competence of subjects to consent despite psychological or cognitive illness. 2. The question of change in personality. Certainly there could be a dark side to this, but change in personality is unequivocally accomplishable. 3. Enhancement. Since obese patients' memory is definitely enhanced as an unintended side effect, the question now is should DBS be offered to improve normal memory? Patients are now requesting this intervention.

There is an international society of stereotactic and functional neurosurgeons. Andres has served as president. There are 500 neurosurgeons in the world doing this work which is not strictly limited to neurosurgeons. It is a multidisciplinary field involving engineers, psychologists, neurologists and others.

Andres' wife Marie is a neurologist. They have two boys, Christopher in the 10th grade and Alexander in the 12th grade. Alexander has become fascinated with scientific discovery. He had an epiphany on a Take Your Child to Work Day when he learned in the lab that science is not simply learning what is already known, but more importantly generating knowledge about the things we don't know. Quoting Yeats, Andres says education should light a fire, not fill a bucket. He is happiest when he is discovering and helping patients. When asked about assuming the role of the Chair of the Neurosurgery Division, he stated that it is an honor to lead what has arguably become the leading neurosurgery division in the world. The challenge is to take it upward from its current exceptional status. "You can't find a better group of residents and faculty".

M.M.