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Could electricity be the key to controlling the symptoms of some neurologic and psychiatric disorders?

Rigid posture, tremor, postural instability, shuffling gait. These are the technical terms you might apply to the man with advancing Parkinson’s disease as he struggles to descend the stairs outside his front door and staggers down his driveway, shoulders hunched, balancing himself precariously between his cane and the car door as he makes his way toward the mailbox at the end of the drive.

The same man on the same day, with his brain stimulator turned on, can walk down the stairs while putting on his jacket, step easily into his car, and drive to the post office. If you saw him on the street, you wouldn’t know he was sick at all.

“It’s a striking outcome, but it’s by no means unusual,” says Duke biomedical engineer and neuroprosthetics expert Warren Grill, PhD.

Brain stimulators, which are devices that deliver steady electrical currents to certain structures in the brain, have been implanted in more than 80,000 patients worldwide. Most commonly used to suppress the symptoms of severe tremor and some cases of Parkinson’s disease, brain stimulation was also recently approved by the FDA for use in medication-resistant obsessive-compulsive disorder.

It’s being explored for treatments of other brain-born illnesses as well, such as epilepsy and depression.

Brain stimulation offers an alternative to medical therapies, which work mostly to block or boost the release and uptake of chemicals that affect neural function. But the brain is an electrical organ as well as a chemical one, and the field of brain stimulation seeks to explore and expand the use of electrical current as a tool for treating disease.

It may even improve the understanding of how the brain does what it does, so that we may better fix it when something goes awry.

Biomedical engineer Warren Grill is investigating ways to improve DBS technology.

The Perks

In deep-brain stimulation (DBS), electrodes are implanted into carefully chosen places in the brain -- for Parkinson’s disease the subthalamic nucleus, an almond-sized structure in the middle of the head, is the usual place -- and a battery-operated pulse generator, implanted just below the clavicle, delivers a steady electric current of about 130 pulses per second through the electrodes.

When the physician finds the right spot and the right frequency, the symptoms go away.

“Unlike with ablation, you’re not killing any tissue when you use DBS -- so you can undo it at any time -- and you can modulate the frequency of the current,” says Duke neurologist Mark Stacy, MD, who along with fellow Duke neurologists Burton Scott, MD, PhD, and Julia Johnson, MD, refers eight to 10 patients a month for the surgical procedure.

The impact on patients’ quality of life can be astounding, especially after medical therapies have failed. “In the people whom you know are going to do well, it’s exciting to know they’re going to have their lives changed,” says Stacy.

Some patients with essential tremor or dystonia don’t get any relief from medication, so for those patients DBS is a real lifeline.

In Parkinson’s patients who do respond well to their medication, DBS can be an excellent extender of treatment, especially after these patients see the inevitable drop in the effectiveness of the drugs. For them, DBS is a way to turn back time; Stacy says it takes the clock back about five years in terms of motor-control symptoms.

DBS does not replace medication in Parkinson’s patients -- it works synergistically with their medication to provide more functional hours in the day.

“As your medicine works, your symptoms ebb and flow,” explains Stacy. “Levodopa [the most commonly prescribed drug for Parkinson’s patients] has a four-hour time of benefit, and it’s very difficult to be on such a tight dosing schedule.”

And since any variability leads to mobility problems, it’s almost impossible to prevent this ebb-and-flow effect. DBS allows these patients to stay better longer, with far fewer interruptions in motor function. Other patients may begin having significant side effects from medication over time.

Stacy was the first person to identify a particularly troubling side effect of the class of drugs -- dopamine agonists -- that are used in Parkinson’s patients: impulse control disorders such as compulsive gambling or other high-risk compulsive behaviors.

In about 15 percent of patients, the dopamine effect leads to behavioral problems that are significant enough to make staying on the drugs a practical impossibility. For these patients, DBS is also an ideal option, says Stacy.

“The effect of DBS treatment on tremor is the most dramatic, but treatment of Parkinson’s may be the most rewarding, because these people have real mobility problems, and with treatment their mobility problems improve.”

Mechanisms Unknown

According to Grill, DBS is “the closest thing I’ve seen in my life to a miracle.” But, in typical miracle fashion, it has yet to be explained -- no one knows why stimulation of the brain causes these dramatic changes to occur, and there’s still much disagreement about what’s going on.

The debilitating spasticity and rigidity of bodies that suffer from brain disorders such as Parkinson’s disease, essential tremor, and dystonia come from highly organized neural firing patterns that interrupt the brain’s ability to generate normal movement in the body.

In Parkinson’s disease, for reasons still unknown, cells in the basal ganglia that produce dopamine begin to die; as levels of dopamine drop, neurons start to fire in synchronous bursts, “like a popopopop,” says Grill. “In a normal brain, there are very few of these kinds of firing patterns.” DBS somehow disrupts the pathologic popopopop.

“We’ve done a good job of eliminating some hypotheses about how DBS works,” says Grill, such as the early thinking that the neurons were being blocked by the artificial electrical current. Grill theorizes that the stimulated neurons are firing in lockstep with the DBS, which prevents those neurons from transmitting any information.

That’s because neural communication is like vocal communication in this way, says Grill -- it’s not just the sound of your voice but the modulation of that sound that creates meaning, which is why we talk and sing instead of just drone to one another.

Grill says the same concept is at work in neural communication, and DBS locks an otherwise misfiring neuron into a sort of neural monotone, shutting down the pathological popopopop.

Grill wants to understand how DBS works because he wants to improve it. For example, like any treatment, DBS has a “dose” -- an optimal frequency, somewhere between 100 to 200 pulses per second, to control the patient’s symptoms with minimized side effects -- and the physician has to program the output.

But for DBS, the number of potential doses is enormous. There are 30,000 possible parameters, Grill says, and which dose will work best for which patient is hard to know. While the side effects of DBS are generally preferable to those of medications, and certainly preferable to the symptoms themselves, they are not negligible.

“Some side effects are overt: unwanted movements, especially in the eyes; disruptions in speech; problems talking, swallowing, or walking,” says Grill. “Also there are more subtle, less understood cognitive side effects, such as decline of verbal memory and changes in mood.”

The side effects are exacerbated at higher frequencies -- as is battery consumption. Most DBS patients have to have their batteries replaced every four years or so; and when a battery costs $25,000 and requires a surgery to replace, prolonging its life is especially valuable.

“If we could figure out how to achieve symptom control at 50 pulses per second instead of 130, we could reduce both battery consumption and side effects,” Grill says.

His team is developing computer models of new lower-frequency firing patterns. After testing them in rat models Grill works with Duke neurosurgeon Dennis Turner, MD, to take those experimental models into humans as quickly as possible, through a unique testing protocol in patients who have to come in for their battery change.

During the window in which these patients are “unplugged” from their current device, Grill can test his models. This has been done in about 60 patients so far, and the group is also working with Emory and Wake Forest universities to add to the patient pool.

“It’s been a really productive approach to getting our discoveries into humans quickly,” Grill says.

Noise in the System

Miguel Nicolelis, MD, PhD

Healthlinerx neurobiologist Miguel Nicolelis, MD, PhD, offers a different explanation for how brain stimulation works: he believes that electrical stimulation disrupts the misfiring neurons’ synchronous pattern, to get those cells off phase and restore the chaos that the brain needs in order to initiate movement.

“The pathological signal in Parkinson’s is very organized,” he says. “It’s like hearing a pure tone.” If their rhythm were drawn on a computer screen, the misfiring neurons would pile up on top of each other, making one big sine wave.

And though a sinus rhythm might look good on a heart monitor, the brain needs less organization in its neurons in order to organize movement in the body.

“The brain likes chaos,” he says. “So we’re inserting noise to disorganize the brain, because that’s how the brain gets things done.”

More important, Nicolelis believes that instead of targeting the brain itself, electrical stimulation may be more effective if it’s delivered to the spinal cord.

Spinal cord stimulation, in which the electrical current is delivered to the top of the spinal cord, has been used since the 1960s for treatment of pain -- in fact, deep brain stimulation as a technology was originally developed for pain patients who didn’t respond to spinal cord stimulation.

Nicolelis’s team has conducted successful studies of spinal cord stimulation in mice with depleted dopamine and Parkinson’s symptoms, which showed that the technique disrupted those symptoms.

The team is currently finishing studies of the technique in primates; based on preliminary results from those trials, Nicolelis expects to start human trials of his spinal cord stimulation protocol as early as 2012.

The concept for the spinal cord stimulation device came from “a moment of sudden insight,” Nicolelis explained when the results of the rodent study were published in Science in 2009.

While analyzing the brain activity of mice with symptoms of Parkinson’s disease, Nicolelis was reminded of some research he’d done in the epilepsy field a decade earlier. The rhythmic brain activity he saw in these animals resembles the mild, continuous, low-frequency seizures that characterize some types of epilepsy in humans.

One way to disrupt the seizure activity in some epilepsy patients is to stimulate the peripheral nerves, which conduct communication between the spinal cord and the limbs, so Nicolelis applied the same concept to Parkinson’s.

“In our studies, we found that the synchronous firing of neurons occurs in different locations throughout the brain,” Nicolelis says. He calls the brain’s normal electrical signals a symphony with no maestro -- our thoughts and behaviors arise from neural firing that takes place across multiple brain structures.

“While the motor cortex is probably where most of it is happening, the spinal cord has access to all structures in the brain,” making it the best location for stopping any bad signaling from the brain. “Also, accessing the spinal cord is much less invasive, it’s easier to do, and it requires less battery power.”

All this means it’s also much more affordable; Nicolelis says it would be so cheap that DBS for movement disorders might become obsolete.

A Future Unknown

Dennis Turner, MD

Turner agrees that, although DBS is an esoteric surgery, its main problem is not its invasiveness, but its cost.

Except for the United States, France, and Germany -- countries where it’s covered by insurance -- it is a self-pay or charity-pay procedure, with the bill being around $120,000 (plus a cool $25,000 every four years for battery replacement).

“It’s a real question, then,” he says. “Is it a lasting therapy if it’s something that most people in the world, even in developed nations, cannot afford?”

Even in the United States, where DBS is covered by insurance, about three-fourths of Parkinson’s and tremor patients who are good candidates don’t want it. Because, well, it’s brain surgery.

Turner’s proficiency at this procedure keeps his patients’ complication rates very low, but as he says, “they’re not zero. And we try hard not to minimize these risks, so that people have an honest view of what they’re getting into.”

Most neurologists are reluctant to recommend brain surgery, says Turner, citing epilepsy as a good parallel example -- for an epilepsy patient, their disease is not degenerative like Parkinson’s, so effective symptom control could be almost like a cure.

“There have been several NIH consensus conferences where everybody agrees that after about two years, if the epilepsy patient isn’t responding to medication, they should be referred for surgical treatment. But the actual time to referral for surgery averages at 17 years. Elective surgery for things that are chronic is not easy for most people, even physicians, to swallow.”

People who do choose DBS tolerate it very well, Turner says, because DBS is imperceptible to the patient after implantation. But Grill, Turner, and Stacy all emphasize that DBS is not a curative procedure.

The specific symptom control that the device offers is durable, says Turner -- for patients with degenerative diseases such as Parkinson’s, motorcontrol symptoms don’t get worse -- but other symptoms (dementia, balance problems) will progress, because the brain is continuing to die around the device.

“DBS works very well,” says Turner. “It’s very successful, but everybody would really rather treat the disease than the symptom. Most of the efforts to treat Parkinson’s still focus on approaches such as cell therapy or gene therapy.”

According to Turner, the closest idea to a cure is gene therapy -- he and Stacy are among several teams working on clinical trials of gene therapies that can produce a lifelong improvement in the neurons that are degenerating in Parkinson’s diseases.

“These are the most promising approaches right now -- meaning we could have possible FDA approval within less than five years,” he says. “That would ultimately be much more satisfying, to find a single treatment that’s lasting.”

Nicolelis suggests that in the future, the use of electrical current could be a similarly lasting therapeutic tool.

“We want to pursue the idea that by disrupting this pathological signal you could somehow disrupt the degenerative process. Think of it as a feedback loop -- cells die, which causes more cells to die. By altering this pathological pattern we might allow some cells to survive, or to even slow down the process as a whole. We don’t have proof of this yet, but that’s a theory we want to explore.”

According to Nicolelis, all neurological disorders -- and psychiatric disorders -- can be treated as diseases of timing. “It’s the timing of neuronal firing that’s key. The only difference among all these diseases is where and how this timing acts on the brain. So correcting the misfiring of neurons might be the most essential treatment in any neurological disorder -- and it might be that electricity is the key.”

Is DBS an Option for your Patient?

Stacy says DBS can make a big difference in patients with advanced tremor or idiopathic Parkinson’s disease (PD), but it’s important to identify the right patients for the procedure.

Physicians might consider referring their patients who meet the following criteria:

  • Tremor patients: poor response to medical therapy

  • PD patients: Levodopa responsive, with good “on” period function

  • Troublesome symptoms, despite optimized pharmacotherapy:

  • Troublesome bradykinesia, rigidity, tremor, or gait in off periods

  • Unpredictable on-off phenomena

  • Motor fluctuations

  • Bothersome dyskinesia

  • No dementia or significant untreated depression

  • Realistic expectations of what the treatment can -- and cannot -- do



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