1

The Scientist Magazine

Tuning the Brain

Deep-brain stimulation is allowing neurosurgeons to adjust the neural activity in specific brain regions to

treat thousands of patients with myriad neurological disorders.

By Andres Lozano | October 28, 2013

(abridged version)

The world’s first neurosurgeries took place about 7,000 years ago in South America with the boring of holes into

hapless patients’ skulls, a process known as trephination. Practitioners of the day believed the source of

neurologic and psychiatric disease to be evil spirits inhabiting the brain, and the way to treat such disorders, they

reasoned, was to make holes in the skull and let the evil spirits escape. The procedure was surprisingly common,

with as many as 1 percent of skulls at some archaeological sites having these holes.

Today, neurosurgeons are still drilling into the brains of patients suffering from neurologic and psychiatric

disorders, but rather than letting evil spirits escape, doctors are putting things in—inserting electrical probes to

tame rogue neurons or to stimulate brain regions that are underperforming. This procedure, known as deep-brain

stimulation (DBS), was first tried for the treatment of pain in the 1960s, and has since been attempted in patients

with numerous other neurologic disorders. DBS is currently approved in the U.S. or Europe for the treatment of

essential tremor, Parkinson’s disease, dystonia (a motor disorder that causes extreme twisting and repetitive

motions), epilepsy, and obsessive-compulsive disorder (OCD). The therapy is currently in clinical trials for

depression, Alzheimer’s disease, addiction, and more.

Each of these disorders is a consequence of pathological activity within a specific brain circuit. In Parkinson’s

disease and dystonia, neurons in the motor circuits misfire, causing aberrant movements of the limbs and torso.

Malfunction in circuits that regulate mood can lead to depression. Impairment of the activity in circuits that

control memory and cognitive function is characteristic of Alzheimer’s disease. DBS targets the precise location

of these malfunctioning neuronal cell bodies or their projections, and either stimulates the region to drive

underperforming circuits, or shuts down overactive or misfiring neurons. The technique has become so advanced

that it can target any region of the brain.

More than 100,000 patients worldwide have received DBS, mostly to treat Parkinson’s disease,

according to Medtronic, a prominent supplier of DBS devices. The implantation of DBS devices is also

aiding in the study of the basic mechanisms underlying various neurological and psychiatric disorders.

During the electrode implantation process, which is often completed using only local anesthesia so

patients remain awake and responsive, surgeons conduct physiological mapping to identify the optimal

brain target. At the same time researchers can also record activity from individual neurons or small

neuronal populations—both at rest and in response to different motor, emotional, or cognitive tasks.

Such medically acquired information is shedding light on the circuitry of neurological and psychiatric

conditions, revealing pathways involved in movement, pain, reward, decision making, and plasticity.

By observing patients’ behavioral changes following the stimulation or inhibition of specific neural

circuits, DBS is helping to explain what goes wrong in the brain to cause symptoms, as well as helping

2

to reveal important commonalities between diverse disorders. The research is also bringing together the

previously disparate fields of neurology and psychiatry, which will undoubtedly benefit patients through

the development of better, more targeted therapies.

Perhaps most importantly, DBS represents a scientific renaissance in systems neuroscience. It is

allowing the functional mapping of previously uncharted neurons and is revealing the behavioral

consequences of the activation or dampening of specific brain circuits. And it is only just getting started.

With more than 700 DBS-related research manuscripts published each year, in all likelihood we will

soon see electrodes being put into place to treat many more disorders of the brain.

A magical cure?

I began my work on DBS in 1990 with my mentor Ronald Tasker at Toronto Western Hospital. In those days, we

used DBS to treat patients suffering intractable pain after strokes or spinal cord injury, and to treat phantom limb

pain in amputee patients. We targeted two areas—either sensory pathways to stimulate pain-processing areas of

the brain, or the brain’s periventricular/periaqueductal regions to modify the perception of pain by modulating the

interaction of different neurons, rather than simply the activation of pain receptor neurons. Electrical stimulation

is usually administered round the clock using small pulses delivered at a rate of at anywhere from 20 to 200 times

per second. Approximately one-half of patients received substantial alleviation of their severe pain. This approach

is somewhat underutilized today, but is worthy of reexamination and further study.

Another disorder for which DBS has proven effective is dystonia, a disorder that causes the body to

twist uncontrollably. Children affected by this disorder get progressively more and more twisted until

they are unable to move their limbs and become crippled. Young patients also develop secondary

complications that can lead to a shortened life span. But stimulating the globus pallidus via DBS often

led children whose trunk and limbs were twisted by pathological neuronal outputs to return to normal or

near normal function within a few weeks. These cases are among the most dramatic improvements

observed following DBS treatment, and highlight the power of brain circuit manipulation in easing

motor symptoms of neurologic disease.

DBS is now an approved therapy for both Parkinson’s and dystonia, but we have only just scratched the

surface of its full potential. The therapy is now rapidly expanding into the psychiatric field, with

ongoing trials for depression, OCD, anorexia nervosa, Tourette syndrome, addiction, and other

disorders. Furthermore, early positive results of DBS in Alzheimer’s patients point to its potential in

treating neurodegenerative disorders, and there is also evidence in laboratory animals that DBS could

even help repair damaged areas of the brain. If true, the therapy could have important applications in a

number of degenerative and traumatic disorders. I envision that we will witness a great expansion of

indications for DBS as we learn more about how the brain works—in sickness and in health. Research

discoveries of several ongoing collaborations, including the Human Connectome Project, which aims to

compile as much neural data as possible and make it available to the world, will support the

development of novel DBS therapies.

Finding the right target

Soon after our work on Parkinson’s disease and dystonia, Helen Mayberg of Emory University and I, along with

other collaborators, realized that we could potentially use this technology not only in circuits that control

3

movement but also in circuits that control other things, such as mood. Given the large and well-defined population

of depressed patients treated in our program at Toronto Western Hospital, we decided to study the effects of DBS

in depression, a highly prevalent disorder that often fails to respond to medication or psychotherapy.

With the guidance of Sid Kennedy and Peter Giacobbe, two psychiatrists who study depression, we compared the

brains of depressed patients with those of healthy controls, using PET scans to look at the blood flow in different

areas, and found that depressed patients showed far less activity in regions of the frontal lobes involved in

motivation, drive, and decision making. Those patients displayed higher activity in Brodmann area 25 (BA25),

known colloquially as the “sadness center” of the brain. We implanted electrodes in BA25 of patients with

depression to see if DBS could tame this overactive region. After several months of continuous stimulation, we

observed a dramatic decrease in the activity of BA25 and a reversal of some of the metabolic abnormalities seen

in the depressed brain. More importantly, we saw very striking clinical benefit in these patients. We are now

conducting a Phase 3 trial of DBS in approximately 200 patients with treatment-resistant depression. Based on our

observations to date, DBS in these patients demonstrates an encouraging profile of safety and effectiveness, and

could soon be approved as a new therapy, albeit a life-long one.

In addition to neuroimaging techniques that can reveal regional brain activity, brain lesioning can also help shed

light on the most important targets for a particular disorder. In brain lesioning, misfiring neurons or their

connections are destroyed, most commonly using a heating probe inserted in the brain. Once the first patients are

treated, data on effectiveness and side effects, in combination with continued neuroimaging, can help further

focus the targets. Lesioning is an alternative to DBS in certain specific cases and can be effective, but it is

irreversible, and any untoward effects can be permanent. Because the dose of DBS at the same site can be

adjusted down if adverse effects emerge, it is considered to be a potentially safer alternative.

Other psychiatric disorders currently under study for their responses to DBS include addiction, bipolar disorder,

and anorexia. In March 2013, for example, my group reported on the treatment of six anorexia patients in a Phase

1 trial of DBS. In this study, we stimulated the subcallosal cingulate, an area that has previously been targeted in

DBS treatment of drug-resistant depression. Three of the six patients showed improvements in their physical

status—benefits that seemed to be mediated by improvements in mood and anxiety rather than caused by a direct

effect on appetite. Despite these promising clinical outcomes, however, many questions remain. The best brain

regions to target with DBS and the most effective way of stimulating those areas are still not clear for most

psychiatric conditions.

Another potential application of DBS that we are exploring is to stimulate areas of memory, which are impaired in

patients with Alzheimer’s disease. We have placed electrodes in an area of the brain called the fornix—the

“highway” in and out of the hippocampus and a key player in memory formation. By stimulating this brain region

with DBS in patients with mild to moderate Alzheimer’s disease, we were able to drive activity in the fornix and

its downstream targets in patients who had demonstrated impaired activity in this region. In other words, DBS

was effectively mimicking the physiological activity of neurons lost as a consequence of neuronal degeneration.

These changes were accompanied by increases in the brain’s glucose consumption in the temporal and parietal

lobes. We are now in a Phase 2 trial of 50 patients with early Alzheimer’s disease to see whether DBS is safe and

effective in this context and whether it can improve their neurological function.