Michael S. Okun, M.D.
September 8, 2014
Deep-Brain Stimulation.
Scribonius Largus, the court physician for the Roman
emperor Claudius, used an electrical torpedo fish in 50 A.D. to treat headaches
and gout. More than 1000 years elapsed before the idea of therapeutic brain
stimulation was rekindled. In 1786, Luigi Galvani demonstrated that he could
conduct electricity through the nerves in a frog's leg. Later, Alessandro Volta
conducted electrical current through wires and built crude but effective battery
sources. Yet none of these experimenters could have predicted the usefulness of
their technology in treating human disease by applying an electrical current
within the human brain.
This year's Lasker–Debakey Clinical Medical Research
Award, announced September 8, recognizes the contributions of two pioneers in
deep-brain stimulation (DBS): Alim-Louis Benabid, a neurosurgeon, and Mahlon
DeLong, a neurologist. Their research and its translation into clinical
practice have improved the lives of more than 100,000 people with Parkinson's
disease or other neurologic or neuropsychiatric disorders.
Typically, people with Parkinson's disease receive
the diagnosis in the sixth or seventh decade of life. Age is the most important
risk factor for the disease, and it has been estimated that 1 to 2% of people
older than 60 years of age are affected. The disability associated with
Parkinson's disease arises from a broad spectrum of motor symptoms (masked
face, soft voice, tremor, small handwriting, rigidity, bradykinesia, dystonia,
balance issues, and shuffling steps) and nonmotor symptoms (depression,
anxiety, apathy, disordered sleep, and cognitive difficulties), as well as
problems of the autonomic nervous system (sexual dysfunction, constipation,
gastrointestinal problems, and orthostatic hypotension). Of every three
patients diagnosed with Parkinson's disease, one will become unemployed within
1 year, and most will be unemployed after 5 years. On average, patients with
Parkinson's disease will spend $1,000 to $6,000 per year on medications, and
their annual risk of hospitalization exceeds 30%.
Before the late 1960s, pioneers sectioned the human
brain's motor pathways, and later investigators intentionally ablated many
basal ganglia regions with alcohol or the application of heat; this approach
met with limited success, however, partly because of inaccurate, imprecise, and
inconsistent targeting. Moreover, intentionally created bilateral brain lesions
frequently led to irreversible deficits in speech, swallowing, and cognition.
This surgical approach faded in popularity with the discovery of levodopa
(dopamine replacement).
Before levodopa's introduction, life for patients
with Parkinson's disease was dreadful. Many were institutionalized. After
levodopa, it became routine for patients with Parkinson's disease to “awaken”
from frozen states, and nearly all were able to live at home. Tremors faded,
stiffness waned, and many patients regained their ability to walk. Yet
important and unexpected challenges emerged. The most worrisome were
dopamine-related, medication-induced complications. Patients began to report
fluctuations (doses wearing off), freezing (especially when walking), and
dance-like movements (chorea), later termed levodopa-induced dyskinesia. Many
reported tremors that did not respond to pharmacotherapy. In addition, there
was a growing realization that levodopa was not a cure and that the disease
progressed despite miraculous “awakenings.”
In the early 1970s, shortly after levodopa's
introduction, Mahlon DeLong began studying a complex and neglected area of the
brain. By the time DeLong joined Edward Evarts' laboratory at the National
Institutes of Health, all the “good stuff” (such as the motor cortex and
cerebellum) had been assigned to other researchers. He was stuck with the basal
ganglia. The paucity of knowledge of even the normal anatomy and physiology of
this part of the brain did not deter DeLong, who published a seminal
description of electrical activity patterns in primate basal ganglia neurons and
a complete description of these neurons' responses to movement.
DeLong, along with Garrett Alexander and Peter
Strick, broke open research on basal ganglia and Parkinson's disease in 1986
when they introduced the segregated circuit hypothesis — the idea that the
basal ganglia and associated areas of cortex and thalamus could be divided into
separate territories, with little functional or anatomical cross-talk.1 This
observation seeded a new understanding of human neural networks, paving the way
for electrical modulation. It also clarified that many of the symptoms of
neurologic and neuropsychiatric diseases could be associated with dysfunction
in specific cortical–basal ganglia brain circuits. DeLong, Hagai Bergman, and
Thomas Wichmann tested this hypothesis by destroying the subthalamic nucleus in
a primate model of Parkinson's disease, and they demonstrated improvement in
disease symptoms.2 Soon thereafter, electricity was introduced as a
modulation-based approach to the brain circuits in Parkinson's disease (see Figure 1
The DeLong “Box” Models of Basal Ganglia Circuitry
and Their Use in Guiding Deep-Brain Stimulation (DBS).
). A French neurosurgeon, Alim-Louis Benabid, would
take the courageous step of leaving a wire that could provide continuous
electrical current inside a human brain.
In 1987, Benabid operated on an elderly man who had
tremor. He had previously created a brain lesion to treat this tremor, but he
was concerned about the potential adverse effects associated with doing the
same in the other hemisphere. And so, in a second procedure, he addressed the
contralateral tremor. He passed a large test probe several centimeters below
the brain's surface. He knew from previous surgeries that low-frequency
stimulation worsened tremor and that faster pulses suppressed it. Benabid left
a neurostimulator in the man's brain. He implanted a wire with four metal
contacts at its tip. This wire, the DBS lead, was then connected to an external
battery source. Benabid and colleagues programmed the device using a small box
with buttons and archaic-looking switches. As simple as the system was, it
turned out to be very powerful, allowing Benabid and Pierre Pollack to
individualize the settings; the results are described in several seminal
articles.3,4
Although the biology and mechanisms underpinning DBS
therapy remain unclear, we now know that normal human brain function is largely
mediated through rhythmic oscillations that continuously repeat. These
oscillations can change and modulate, ultimately affecting cognitive,
behavioral, and motor function. If an oscillation goes bad, it can cause a
disabling tremor or other symptom of Parkinson's disease. Rogue brain circuits
stuck in states of abnormal oscillation in many diseases have become candidates
for DBS therapy. Changes in neurophysiology, neurochemistry, neurovascular
structures, and neurogenesis may also underpin the benefits of DBS therapy.5
Before therapeutic DBS was developed, neurologists,
neurosurgeons, psychiatrists, and rehabilitation therapists labored largely in
isolation from one another when treating patients with Parkinson's disease. DBS
therapy's success spurred the formation of multidisciplinary teams, whose
members evaluate candidates for DBS and together personalize the therapy. This
personalization includes selecting, on the basis of symptoms, the brain regions
to target and planning preoperative and postoperative care. Although DBS teams
typically have many members, I believe the most important element for success
has been the partnership between neurologist and neurosurgeon. It is therefore
fitting that the Lasker Award for DBS therapy has been given to a neurologist
and a neurosurgeon.
Smaller, sleeker, more energy-efficient units are on
the horizon. Better lead designs will permit more precise current delivery.
Real-time monitoring of the neural-circuit physiology is driving the field
toward smarter technologies. Remote monitoring and adjustment of devices may
become possible. In its current form, however, the technology has several
limitations. Current can spread into unintended brain regions, causing side
effects, and DBS usually doesn't effectively treat all symptoms. Most commonly,
the battery source for neurostimulators has been placed in the subclavicular
region (see Figure 2
Devices for DBS.
), but this configuration has been associated with
high risks of lead fracture and infection.
Nevertheless, DBS has had an enormous effect on the
treatment of Parkinson's disease. It has also been used to treat essential
tremor, dystonia, and epilepsy and in experimental treatments of
obsessive–compulsive disorder, depression, Alzheimer's disease, and Tourette's
syndrome (see interactive
graphic, available with the full text of this article at NEJM.org).
DBS therapy is usually considered only after all other treatments have been exhausted,
but becoming “bionic” has provided many patients with a new lease on life.
Thanks in large part to the contributions of two extraordinary scientists, we
have entered the era of human neural-network modulation.
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