Focus on: Neuromodulation

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Photo courtesy of St Jude Medical

Over the past decade, neuromodulation has grown into a wide and varied field with approvals for additional applications increasing every year. NeuroNews now speaks to four thought-leaders in the neuromodulation arena about the research priorities, challenges and potential areas for growth.

Neuromodulation is being tested as a potential treatment for various different diseases and ailments. In your view what are the research priorities in the area of neuromodulation, and why?


Timothy Deer:
The priorities can be classified into three separate groups:  we need to complete the current randomised prospective comparative studies on new waveforms and spinal cord targets. These studies will improve the validity of the field and provide a framework for future use. Secondly, we need to consider the role of neuromodulation in disease management. Early work in heart failure and vascular disease is very promising. In the spine and brain, work for many diseases could become the standard of care. Lastly, the replacement of drugs with electrical current could be a valuable cost-effective option for inflammatory diseases, and other systemic illnesses.

Ali Rezai: Research that advances our understanding of the neural networks and circuitry underlying various brain disorders is fundamentally important for guiding new applications of targeted neurostimulation. Important areas of opportunities for discovery in brain neuromodulation involve deep brain stimulation studies in patients with cognitive and behavioural disorders such as depression, anxiety, addictions, Alzheimer’s disease, eating disorders, and traumatic brain injury, as well as stroke motor recovery. Another area of significant opportunity for translational research is autonomic nervous system neuromodulation. This has expanded the scope of neuromodulation by bringing in various other specialists such as urologists, cardiologists, otolaryngologists and others. Clinical trial applications encompass migraine and cluster headaches, urinary incontinence, heart failure, arrhythmias, rheumatoid arthritis, and gastrointestinal disorders.

Marc Russo: The key research priorities are to document the efficacy of neuromodulation in the different indications it has found success in and to then additionally document cost-effectiveness and healthcare cost utilisation compared to the alternatives. We need an evidence base that is second to none in the medical device industry field.

Konstantin Slavin: There should be two priorities, in my opinion—(a) strengthening of the body of evidence for existing indications and (b) development of new indications. Stronger evidence of efficacy (and cost-effectiveness) is needed to maintain the access to neuromodulation for our patients with chronic pain, movement disorders, epilepsy and other currently approved indications. As evidence-based medicine is gaining momentum, many of our approaches that were never properly tested have been questioned and sometimes denied by payors and insurers—very often despite several decades of positive experience. At the same time, development of new indications—such as various pain conditions (headaches, back pain, fibromyalgia), cardiovascular, gastrointestinal and genitourinary disorders, dementia, depression, post-stroke neurological deficits—will ensure continuous growth of neuromodulation modalities and, subsequently, further improvement of quality of life for our patients. 

What are the challenges and complications associated with neuromodulation?


Ali Rezai:
One challenge impacting the growth of neuromodulation is the cost of the implantable devices and limitations in reimbursement, thus limiting access for patients who can benefit from these therapies. In addition, improvements in patient selection criteria, guidelines, development of registries, and objective biomarkers applications are needed, as well as studies of cost-effectiveness and quality of life with neuromodulation.

Marc Russo: The challenge is to effectively disseminate knowledge about neuromodulation to the large number of physicians and surgeons who are uninformed on it. There is no reason why it should not be a routine procedure for the right indications, but right now it is believed that barely 5–10% of patients who need or qualify for this therapy actually get access to it. The commentary on complications is that we need both device and procedure related complications to come down. In the field of cardiac rhythm management they are a fraction of what they are in neuromodulation. That speaks to the younger history of the specialty and the lower absolute volumes of production.

Konstantin Slavin: Challenges and complications of neuromodulation are related to several things that have to do with clinical, technological and theoretical aspects of this non-destructive and minimally invasive approach. The main issue remains proper patient selection, as individual responses to our neuromodulation procedures vary from person to person. The second major challenge is in relative shortage of basic science research that could better explain the mechanisms of action of our interventions and perhaps aid in development of new technological breakthroughs. Finally, the technology itself presents a challenge as a large part of neuromodulation complications and unsatisfactory outcomes may be explained by device-related issues; here the hope is in ongoing progress in material science, development of indication-specific hardware, and emphasis on individually-tailored interventions.

 

What are the key things to keep in mind when developing standards of practice in neuromodulation?


Ali Rezai:
Key features for developing standards of practice in neuromodulation are strong neuroscience and scientific rationale guiding new clinical applications and clinical trial design. Patient selection standards are also crucial variables. Patient selection should take into account accurate diagnosis, disease progression and chronicity, medication intractable nature, medication side effects and the use of other available treatment options prior to consideration of neuromodulation. Furthermore, patient and family clarity about outcome expectations, limitation of benefit, and clear understanding of the side effects has to be carefully considered.

Marc Russo: The biggest improvements in medicine come not from pushing up the top 1%, they come from pulling up the bottom 20%—Atul Gawande showed this clearly in his book. The field needs to ensure the practice standards it has produced (NACC and PACC guidelines as well as national guidelines) are well disseminated and then, most importantly, followed. This comes through audit both within and outside of one’s own practice. The International Neuromodulation Society is leading the way in coordinating this around the world.

What has the most important development/breakthrough in neuromodulation been?


Timothy Deer:
In the past 40 years the advancements were incremental and slow to develop. In the past few years advancements in current delivery and new targets have given us potential changes in the field that could lead to dramatic improvements in patient efficacy and safety.

Ali Rezai: One breakthrough in neuromodulation has been the visible and clear success of deep brain stimulation for movement disorders, resulting in over 100,000 deep brain stimulation implants worldwide. Another is the use of implantable infusion pumps and their safety and reliability for delivery of baclofen to treat spasticity and for morphine and other medications for chronic pain.

Marc Russo: This would have to be the introduction of multiple medical device companies into the field and the innovation and competition they have brought as a result. Without that, the field would have stultified. As it is, it is a vibrantly growing and advancing field with a rate of change that is unparalleled in my 20 plus years in the field.

Konstantin Slavin: There are many recent developments that are expected to change our practice of neuromodulation within next several years—these include development of new stimulation paradigms (such as paraesthesia-free stimulation for pain), new stimulation principles (such as closed-loop or adaptive stimulation), new stimulation targets (dorsal root ganglia, cerebral, spinal and peripheral neural structures), new technological developments (rechargeability, larger number of stimulation electrodes, directional stimulation, simultaneous stimulation and recording, MRI-compatibility, miniaturisation). Personally, I was most impressed very recently by a development of an implanted device that was powered by the body itself—earlier this year, there was a report of a new pacemaker that is powered by the patient’s heart; I am sure there will be neuromodulation devices that are powered by the body temperature, electrical signals of the nervous system, or some other activity of the patient.

 


Where are the key opportunities for growth within the area of neuromodulation?


Timothy Deer:
Improved public awareness is critical. Many patients feel that oral opioids are the only option for severe chronic pain. Family physicians also are often unaware of the options for their patients. In addition to these issues we should strive for improvements in globalisation to address pain in patients in regions of the world where advanced therapies are limited or unavailable.

Konstantin Slavin: I feel that the biggest opportunity in neuromodulation is in better penetration of the market related to currently existing indication: even by best estimates, neuromodulation today is used in less than 5-15% of patients depending on indication. I do believe that one day we will see a situation when every candidate for neuromodulation procedure will be at least given an option of having it: similar to what is happening now when it comes to cardiac pacemakers. In addition to this, new indications (headaches, depression, dementia, low back pain) may eclipse by volume all current neuromodulation uses due to very high prevalence of these potentially treatable conditions.

What are the key ongoing studies?


Ali Rezai:
There are many ongoing investigational studies worldwide. Several key studies of peripheral and autonomic nerve stimulation are evaluating new applications of neurostimulation technology for urinary incontinence, migraine and cluster headaches, heart failure, asthma, and rheumatoid arthritis. The use of high frequency spinal cord stimulation and dorsal root ganglion stimulation is of interest with several studies looking in chronic pain patients. Additional spinal cord stimulation studies are evaluating the potential for movements and gait improvements in those with spinal cord injuries. Deep brain stimulation is being investigated in Alzheimer’s, eating disorders, addictions, and traumatic brain injury. Additionally, brain implants are being used for chronic neural recording for brain machine interface applications in patients with spinal cord and brain injury. 

Marc Russo: In the pain arena we are now moving into healthcare cost-effectiveness. That is paramount in a dollar constrained healthcare world. Outside of this area there are important trials being conducted in chronic headache, chronic angina and congestive heart failure, for example, as indications of organ system optimisation.

 

What new techniques/technologies are you keeping an eye on?


Timothy Deer:
I am keeping my eye on several new technologies: new methods of stimulating the sacral nerves to treat incontinence and pelvic disorders; new methods of treating congestive heart failure with spinal cord stimulation; brain machine interfaces; and electrical pharmaceuticals to treat systemic diseases. 

Ali Rezai: Recent technological advances are allowing for the use of micro-implantable neuromodulation devices that are miniature, minimally invasive, and not attached with connecting wires to pacemaker batteries.  These micro-stimulators are remotely powered and managed via hand held external systems analogous to smart phone-like devices. Applications for urinary incontinence, cluster and migraine headaches, and other pain conditions are being explored. With maturation of this technology, applications for many other areas will be forthcoming.

Marc Russo: Not every new technology will turn out to be a winner. There will be a natural selection of what really does make a difference and ‘moves the needle’ rather than being simply incremental. Two areas I am looking at with excitement right now are Sti mwave Technologies which can eliminate the need for an implanted battery via microwave transponder technology, and down the line, Nicta which are developing a feedback loop sensing system for optimised spinal cord electrical activation.

 

 

Timothy Deer is clinical professor of Anaesthesiology at West Virginia University, USA

Ali Rezai is Stanley D and Joan H Ross chair in Neuromodulation at the Ohio State University, Wexner Medical Center, Columbus, USA

Marc Russo is a fellow of the Australian and New Zealand College of Anaesthetists and director of the Hunter Pain Clinic, Newcastle, Australia

Konstantin Slavin is chief of Stereotactic and Functional Neurosurgery Section, Department of Neurosurgery, University of Illinois at Chicago, USA