© THOM GRAVESThe 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.
Deep-brain stimulation represents a scientific renaissance in systems neuroscience, allowing the functional mapping of previously uncharted neurons.
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 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?
© THOM GRAVESI 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.
We leveraged this experience and combined it with conceptual advances and surgical developments in the field of Parkinson’s disease, and soon applied DBS to treat that disease and other movement disorders. Many of our Parkinson’s patients, despite the best available medical treatment, were disabled by tremor, rigidity, and slow movements, or by involuntary movements caused by the common Parkinson’s drug levodopa (L-Dopa), which boosts dopamine levels in the brain. We implanted electrodes—usually one in either hemisphere of the brain—in one of several targets: the thalamus, a region critical for relaying motor commands and feedback to and from the cerebral cortex; the globus pallidus, which helps regulate voluntary movements; or the subthalamic nucleus, an area just below the thalamus that is also involved in voluntary movement. (See illustration above.) We found that the best target depended on a patient’s symptoms. In the case of tremor, stimulation of the thalamus is very effective. We suspect that the tremor is caused by approximately 25,000 neurons firing in synchrony. We treat the rigidity, slowness of movements, and drug-induced involuntary movements by implanting electrodes in either the subthalamic nucleus or globus pallidus. Stimulating the neurons to disrupt the synchrony can completely eliminate or significantly ameliorate these symptoms for the duration of the stimulation in most patients without any observable adverse effects.
DBS is now an approved therapy for both Parkinson’s and dystonia, but we have only just scratched the surface of its full potential.
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
COURTESY OF ANDRES LOZANOSoon 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 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. (See illustration above.) 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.1 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.
Comparisons of PET imaging from OCD patients and healthy control subjects have shown hyperactivity in the cortico-striato-thalamo-cortical circuit. This network links the basal ganglia—neuronal clusters critical for the control of motor function and motor learning—to the motor and premotor cortices that dictate actual movement. Other imaging studies have revealed heightened activity of the orbitofrontal cortex, a region involved in decision making, and the caudate nucleus, part of the brain’s learning and memory system, when a patient’s OCD symptoms are aggravated. Based on these results and clinical experience studying the effects of lesions in these areas, multiple brain regions have been targeted by DBS in OCD patients. (See illustration above.) So far, the results are promising: at least half of the patients treated with DBS showed a 40–60 percent decrease in OCD symptoms,2 and several trials are pushing this therapy toward approval.
DBS has also shown promise in the treatment of Tourette’s syndrome. Early studies have targeted the medial thalamus including the centromedian-parafascicular (CM/pf) complex, a crucial nexus in the brain circuit that includes the striatum; the globus pallidus, which is involved in voluntary movement; and the thalamus. And the results have been positive, with patients in one study demonstrating a 50 percent reduction in the severity of the tics that characterize the disorder.3 Other researchers have targeted the bilateral internal globus pallidus (GPi) with DBS, and still others the external globus pallidus (GPe). All of these studies yielded positive findings.
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.4 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.
In addition to developing into a broadly applicable therapeutic strategy, DBS is also proving its worth as a research tool.
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. (See illustration above.) 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. (See brain scans.) 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.
Probing brains for research
In addition to developing into a broadly applicable therapeutic strategy, DBS is also proving its worth as a research tool. In the treatment of movement disorders such as Parkinson’s disease, researchers have found that stimulating activity in the basal ganglia and thalamic nuclei affects speech and language. Indeed, DBS had previously been noted to affect certain linguistic functions, such as grammar.5 While this is an obvious concern in terms of the safety of this treatment, it could also serve as a unique opportunity for language researchers, who can monitor DBS-treated patients for clues regarding how the brain processes language.6
In addition to what researchers can glean from the ongoing clinical work, DBS in rodent models is also proving useful for elucidating the mechanisms by which the technique provides benefits to patients suffering from myriad neurological disorders. In the field of depression research, numerous groups have taken to stimulating different regions of the rodent brain to identify local tissue inactivation, the modulation of fiber pathways, the serotonergic system, and brain-derived neurotrophic factor as possible corollaries to the antidepressant effects of DBS in humans.7 Other researchers are studying DBS in animal models of Parkinson’s disease, dystonia, epilepsy, pain, cognitive disorders, OCD, and depression. While stimulation of animal brains is not a new technique, the success of DBS in the clinic has undoubtedly fueled this area of research.
For these and other reasons, DBS must be studied using a multidisciplinary approach. Engineers, imaging scientists, basic scientists, neurologists, psychiatrists, neurosurgeons, and others must come together to embrace this increasingly successful clinical tool and promising research strategy. At the interface of these multiple disciplines lies much excitement and hope. In time, I believe that just as the neurosurgeons of antiquity hoped to do, we will be able to chase more of these evil spirits out of the brain, and as a consequence, help many more patients.
Andres Lozano is a professor and the Dan Family Chairman in Neurosurgery at the University of Toronto. He also holds both the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery at University Health Network and a Tier 1 Canada Research Chair in Neuroscience. He is also a consultant for Medtronic, Boston Scientific, Functional Neuromodulation, and St. Jude Medical, Inc.
- H.S. Mayberg et al., “Deep brain stimulation for treatment-resistant depression,” Neuron, 45:651-60, 2005.
- D. Denys, M. Mantione, “Deep brain stimulation in obsessive-compulsive disorder,” Prog Brain Res, 175:419-27, 2009.
- L. Ackermans et al., “Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome,” Brain, 134:832-44, 2011.
- N. Lipsman et al., “Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial,” Lancet, 381:1361-70, 2013.
- L. Phillips et al., “Subthalamic nucleus deep brain stimulation impacts language in early Parkinson’s disease,” PLOS ONE, 7:e42829, 2012.
- F. Klostermann et al., “Learning about language and speech from deep brain stimulation,” J Neurolinguistics, 25:63-73, 2012.
- C. Hamani, J.N. Nobrega, “Preclinical studies modeling deep brain stimulation for depression,” Biol Psychiatry, 72:916-23, 2012.