Advancing Applications of Closed-Loop Neurostimulation

Neurostimulation, including spinal cord neurostimulation, has been an established treatment for epilepsy, Parkinson’s disease, and chronic neuropathic pain for years.

In 1997, the FDA approved deep brain stimulation (DBS) to treat tremor and vagus nerve stimulation (VNS) for epilepsy.^1,2 But these are all examples of open-loop systems, as are most of the neurostimulation treatments used today.^1,2

Unlike open-loop neurostimulation — a preprogrammed treatment that does not automatically adapt to changes in activity or symptoms — closed-loop systems are designed to sense physiologic changes and adjust treatment accordingly, resulting in more effective treatment and fewer side effects.^1,3

“An open system does what it does, like an old fashioned pacemaker. A closed-loop system probes and adapts, like a modern pacemaker or defibrillator. Closed-loop systems are exciting, but brain systems are more complex than cardiac systems. We are still working on where to place them and how to trigger them,” said Michael Pourfar, MD, co-director of the Center for Neuromodulation at NYU Langone Medical Center in New York City.

Neurostimulation for Neuropathic Pain

Spinal cord stimulation (SCS) is a widely used treatment for intractable and chronic neuropathic pain. SCS works by interfering with pain signals as they travel through the spinal cord. Open-loop SCS may provide too much or too little therapy and does not change with body position, and may also require multiple adjustments during the day to be effective.¹

New technology such as the RestoreSensor, an implantable, closed-loop SCS system recently approved by the FDA, uses an accelerometer to sense eight body positions and adjust stimulation accordingly. In a recent clinical trial, more than 80% of patients reported improved comfort during position changes, and almost 70% reported improved activity levels with the closed-loop system compared to an open-loop system.¹

Neurostimulation for Epilepsy

Despite the many new antiepileptic drugs introduced in the past 20 years, many patients with partial seizures are still drug-resistant.² Open-loop vagus nerve stimulation (VNS) and closed-loop responsive cortical stimulation (RNS) have now been approved for treatment of drug-resistant partial seizures.¹

VNS uses a device implanted in the chest, like a pacemaker, in which a wire is used to stimulate the left vagus nerve in a programmed periodic open loop. Patients can also use a magnet to trigger stimulation if a seizure aura is detected. Although the exact mechanism of action remains theoretical, clinical trials suggest seizure reduction of about 24%.¹ Additionally, the ascending pathway of the vagus nerve is polsynaptic, and it may work at many levels.²

RNS, in which the primary goal is not prevention but early termination, involves an implanted intracranial device that provides responsive stimulation to one or two detected seizure foci. Stimulation is triggered by spikes and slow wave changes in brain activity. During the open-label phase of a pivotal clinical trial of RNS, median reduction of seizures was 53% at two years after implant compared to baseline.¹

“Closed-loop neurostimulation systems for epilepsy are more advanced than they are for movement disorders. Closed-loop systems can read brain activity, detect, and abort seizures,” said Pourfar.

Neurostimulation in Parkinson’s Disease

A 2014 review of closed-loop neurostimulation for Parkinson’s disease, published in Neurosurgery Clinics of North America, concluded that closed-loop stimulation is preferable to open-loop stimulation, because it has a less disruptive impact on cognitive processes. But closing the loop in movement disorders is still a work in progress.³

“Open-loop stimulation is available to treat Parkinson’s, essential tremor, and dystonia. The systems are implanted in the operating room and a clinician tests the implanted electrodes to find the points where symptoms are relieved before side effects start. The patient then test drives the system and returns for adjustments. Much depends on the clinician’s judgment and experience,” said Adam Hebb, MD, neurosurgeon at the Colorado Neurological Institute, and author of the review.

Open-loop DBS for advanced Parkinson’s disease involves a battery-operated, subcutaneously implanted pulse generator that delivers electrical stimuli to electrodes in the cortical-basal networks. The exact mechanism of action is unclear, but DBS has been shown to reduce motor scores on the United Parkinson’s Disease Rating Scale by 50%, and more than 80,000 patients have benefited from the treatment.⁵

So far, a closed-loop neurostimulation system has only been developed for investigational use. One possible trigger being explored is the beta frequency band of the local field potentials in the subthalamic nucleus. Suppression of beta activity here has been associated with improved motor performance.^1,3,5

“Another marker for DBS could be a patient’s behavioral state. Stimulation could be customized for sleep, activity, and motion. It is hoped that closed-loop systems will reduce DBS side effects. These include disturbances in gait, balance, speech, and verbal fluency. It is not too farfetched to envision closed-loop stimulation enhancing cognition,” said Hebb.

Another area of research for Parkinson’s is closed-loop cortical stimulation instead of DBS, which may be a less invasive option. In any case, closed-loop neurostimulation for Parkinson’s and other movement disorders remains investigational.⁵

“This is the first year we are recording brain activity. Closing the loop on Parkinson’s disease will probably need five years of investigational data and another five years of clinical trials. So we are probably still 10 years away,” said Hebb.

Advantages of Closing the Loop

While there are already many known clinical advantages of closed-loop neurostimulation for diseases like epilepsy, chronic pain, and movement disorders, some of the most beneficial aspects are evident in a patient’s quality of life, including more independence and less day-to-day burden, including maintaining their neurostimulation systems. “An important advantage of closed loop systems is that they save battery power. Batteries can be smaller and need to be replaced less frequently,” says Pourfar.

Despite the advances made in neuropathic pain and epilepsy, there is much progress to be made for movement disorders. Researchers continue to be challenged with the task of determining physiologic markers for specific symptoms and finding the best anatomic targets for stimulation. Still, clinical experience from existing symptoms supports the notion that closed is better than open.¹

“Closed-loop stimulation for movement disorders is coming. Other disorders that may respond to these systems include major depression, OCD, Tourette syndrome, and cluster headaches,” said Hebb. He and his team at the Colorado Neurological Institute are currently recruiting patients for a trial to investigate brain activity that can be used to customize DBS. Learn more about the trial here.

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts. This article was medically reviewed by Pat F. Bass III, MD, MS, MPH.

References

1. Sun FT, Morrell MJ. Closed-loop neurostimulation: the clinical experience. Neurotherapeutics. 2014;11(3):553-63.
2. Bergey GK. Neurostimulation in the treatment of epilepsy. Exp Neurol. 2013;244:87-95.
3. Hebb AO, Zhang JJ, Mahoor MH, et al. Creating the feedback loop: closed-loop neurostimulation. Neurosurg Clin N Am. 2014;25(1):187-204.
4. Schacter SC, Sirven JI. Vagus nerve stimulation (VNS). Epilepsy Foundation. Available here: http://www.epilepsy.com/learn/treating-seizures-and-epilepsy/devices/vagus-nerve-stimulation-vns
5. Beuter A, Lefaucheur JP, Modolo J. Closed-loop cortical neuromodulation in Parkinson’s disease: An alternative to deep brain stimulation?. Clin Neurophysiol. 2014;125(5):874-85.