TORONTO—The number of viable applications for deep brain stimulation continues to expand, with investigators now targeting a host of neurologic and psychiatric disorders. Initially applied as a treatment for chronic pain and movement disorders such as Parkinson’s disease, deep brain stimulation is in various stages of research for epilepsy, headache, multiple sclerosis (MS), and Alzheimer’s disease, as well as Tourette syndrome, depression, and obsessive-compulsive disorder. Other potential applications include obesity and eating disorders, substance abuse, violent behavior, and patients who are in a minimally conscious state.
“No neuron is safe from a neurosurgeon,” said Andres M. Lozano, MD, PhD, at the 62nd Annual Meeting of the American Academy of Neurology. “We can really go anywhere in the brain with considerable safety…. We can either drive a circuit, or we can suppress pathologic activity within circuits. And this is based on where we put the electrodes, how we stimulate, and what neural elements are being affected by the stimulation.” Dr. Lozano is a Professor in the Department of Surgery, University of Toronto.
Thus far, the FDA has approved deep brain stimulation for Parkinson’s disease, essential tremor, and dystonia. The procedure involves surgically implanting a device that delivers carefully monitored electrical stimulation to precisely targeted areas in the brain that control movement and muscle function. Dr. Lozano’s research has focused on the use of deep brain stimulation for Parkinson’s disease, depression, and Alzheimer’s disease.
Parkinson’s Disease
For the past two decades, deep brain stimulation of the subthalamic nucleus (STN) or globus pallidus interna (GPi) has been effectively used to treat the cardinal motor symptoms of Parkinson’s disease—tremor, rigidity, postural instability, and bradykinesia—after medication has failed. However, the main drivers of disability—nondopaminergic symptoms such as gait and postural disturbance—are still in need of an effective treatment and remain a target, noted Dr. Lozano.
In a study involving six patients with advanced Parkinson’s disease and gait and postural abnormalities, Dr. Lozano and colleagues implanted electrodes in the pedunculopontine nucleus of all subjects. At three and 12 months after the procedure, patients had a significant reduction in falls in the on and off medication states.
“The main thing that we are finding is that the patients are falling less,” said Dr. Lozano. “We think that this is promising enough, that it is worthwhile examining the pedunculopontine nucleus as a target in patients with Parkinson’s disease who are falling despite best medical or best surgical management…. Because this symptom is so important and we have little else, it is really worthwhile to study this problem to see [if there are] benefits and whether it is safe and effective to treat patients in the pedunculopontine nucleus.”
Psychiatric Disorders
The most promising use for deep brain stimulation may be the treatment of psychiatric disorders, according to Dr. Lozano. He noted that depression, for example, is about 30 to 40 times more common than Parkinson’s disease. “And just as people are resistant to medications in Parkinson’s disease, roughly 10% to 15% of patients with depression fail all medical therapy, psychiatric talk therapy, and electroconvulsive therapy,” said Dr. Lozano. “So we have 10% to 15% of the depression cohort who are potentially failing all these interventions for depression for which we should examine novel therapies.”
Using PET scans, Dr. Lozano’s group found that patients with depression have hyperactivity in the subgenual cingulate gyrus-25 area of the brain. “And not only that, their frontal lobes are shut down,” said Dr. Lozano. “So ‘area 25’ is the sadness center of the brain. In patients with depression at baseline, they have hyperactivity in this area of the brain that regulates mood and is responsible seemingly for sadness. We have a hyper-sadness state in depression. Concomitant with that, we have the frontal lobes that are shut down, and we think this is the reason why patients lack motivation, why they are withdrawn, why they don’t engage, and why they have executive dysfunction.”
In a follow-up study, Dr. Lozano’s group stimulated the subcallosal cingulate gyrus in 20 patients with severe depression. Six months after surgery, 60% of patients were responders (those achieving a 50% or greater reduction in the Hamilton Rating Scale for Depression) and 35% met criteria for remission (score of 7 or less), benefits that were largely maintained at 12 months. “After about a year, we have between 50% and 60% of patients who get this kind of robust response in their depression scores,” said Dr. Lozano.
Dr. Lozano and colleagues are organizing a multicenter, randomized trial with 200 patients with severe depression in 18 centers in the United States to determine the safety and effectiveness of the procedure. If the study yields positive results, “then this will become a new therapy to really modulate these mood circuits in the brain and to treat these patients with severe depression,” he said.