Deep brain stimulation therapy

Neurological and psychiatric illnesses continue to cause major disability despite currently available treatment options. With this background of unmet treatment need, important advances in structural and functional brain imaging, the understanding of the circuitry of neurological disease, and neurosurgical techniques and equipment have led to the emergence of deep brain stimulation (DBS) as an effective therapeutic option.

Deep brain stimulation was first tested in animal experiments about 70 years ago and has been used in human subjects, mainly to treat movement disorders—particularly Parkinson’s disease—for the past 20 years. It is now available in most major medical centres. More than 80 000 patients have undergone such stimulation to date,1 and 8000-10 000 new patients are treated each year.

Deep brain stimulation involves implanting indwelling electrodes within specific brain circuits to modulate the activity of those circuits, either to suppress pathological neuronal activity or to drive underactive output; an analogy would be moving the dial to a chosen radio station and adjusting the volume when the sound is too low or too loud. The target location is most often chosen using structural brain imaging, usually computed tomography or magnetic resonance imaging. Occasionally, a potential target is identified as an area of abnormal activity using functional imaging or electrophysiology. This last approach has been used to guide electrode placement for patients with depression, cluster headache, and epilepsy.2 3 4

Electrodes are commonly placed with patients fully awake, which allows the surgeon to pinpoint the precise location in the brain using microelectrode recordings of neurones at the target. The surgeon can also gauge the patient’s response to stimulation, which helps guide the final placement of the electrodes. The electrodes are then connected to an implanted pulse generator (along the lines of a standard cardiac pacemaker), which can be programmed to deliver continuous stimulation for several years—batteries last four to five years or longer with recharging. The level of stimulation is adjusted to optimise the desired outcome and minimise unwanted side effects. The activity of an entire interconnected brain network can be manipulated in this way because the current acts locally, at the site of application, and remotely, at sites that are anatomically connected.

Randomised and non-randomised studies of stimulation plus medical treatment versus medical treatment alone in patients with Parkinson’s disease, essential tremor, and dystonia have shown that it has striking clinical benefits.5 6 7 8 9 On this basis, a recent expert consensus statement on stimulation for Parkinson’s disease concluded that the best candidates for treatment are patients with medically intractable motor fluctuations, levodopa induced dyskinesias, tremor, or intolerance of the adverse effects of drugs.10 It also suggested that procedures should be conducted by experienced multidisciplinary teams (comprising neurologists, brain imaging scientists, basic neuroscientists, psychiatrists, and neurosurgeons).

The optimal site for placement of electrodes in patients with Parkinson’s disease remains controversial. Traditionally, the subthalamic nucleus has been the location of choice, but stimulation of the internal segment of the globus pallidus has shown similar clinical benefits, with possibly a more favourable profile of psychiatric adverse effects.5

However great the potential benefits of deep brain stimulation, they must be considered alongside its risks. Patients risk a roughly 1% incidence of serious intraoperative events (such as cerebral haemorrhage or stroke); stimulation related adverse effects (such as paraesthesias, dysarthria, and motor contractions), which are usually reversible if stimulation is reduced or stopped; and ongoing long term complications that are related to the hardware, such as breakage, malfunction, and infection, which can occur in 5-10% of patients.11

What does the future hold? Accumulating evidence suggests that the signs and symptoms of several other neurological disorders—including depression, epilepsy, and Alzheimer’s disease—are associated with pathological activity in brain circuits or the failure of normal brain networks, although the potential causes vary.

Almost all brain circuits can be accessed for the insertion of electrodes and their activity modulated using targeted brain stimulation. The potential for applying deep brain stimulation therapy in patients with non-motor neurological and psychiatric disorders is the subject of extensive research. The National Institutes of Health clinical trial registry (www.clinicaltrials.gov) alone lists some 170 clinical trials of stimulation that are active or at some stage of completion. Conditions for which the use of stimulation is being examined include epilepsy, minimally conscious states, depression, bipolar disorder, anorexia nervosa, obsessive compulsive disorder, Tourette’s syndrome, addiction, pain, Alzheimer’s disease,12 and even obesity and the central regulation of blood pressure. Because stimulation can be turned on or off, double blind studies where patients with implants are randomly assigned to active or sham stimulation are possible, and this is an increasingly popular feature in the design of such clinical trials.

Progress will probably come from the collaboration of scientists from different disciplines: neurology, neuroscience, brain imaging, neurosurgery, and mental health.