Medical

Coming to a Future Near You: Neuromodulation, a Multi-Specialty Field

Neuromodulation is an exciting therapy for improving neurological ailments. When I graduated medical school in 2009, I had no idea what “neuromodulation” meant or the surgeries it encompasses despite my interest in neurosurgery. Even today, I hear about practicing physicians seeing a spinal cord stimulator for the first time because they had no exposure during medical school, or experience managing chronic-pain patients. There is a lack of education in medical school about neuromodulation, as well as multidisciplinary pain treatment, despite huge unmet need. This article introduces this fast-growing field.
What is neuromodulation?
Neuromodulation is an emerging class of therapies that directly treat the nervous system, often through small implanted devices that target a specific area, to rebalance the activity of neural circuits and manage symptoms. These technologies include implantable as well as non-implantable devices that deliver electrical, chemical or other agents to reversibly modify brain and nerve cell activity.
Neuromodulation is:
· Highly targeted to specific areas of the brain, spinal cord, or peripheral nerves, rather than systemic throughout the body like pharmaceutical treatments
· Highly reversible, allowing physicians to immediately cease treatment with the removal of the stimulating device
· Continuous, improving therapeutic compliance over techniques that rely on fixed intermittent dosing
Learning about neuromodulation
I found out about neuromodulation during my early years of neurosurgery residency and I discovered hope for easing pain via surgery among patients with chronic conditions who cannot gain relief from medications. It fits into my overall interests in medicine since it is rewarding to see patients who had poor quality of life and limited daily function due to pain get better with relatively minor surgical procedures. At the end of this article, I will list some resources for learning more about the field, and encourage readers to share what they know about training programs in the discussion thread.
In addition, there is a concurrent need for patients to gain familiarity with this intervention.
Types of neuromodulation procedures
The most common neuromodulation therapy is spinal cord stimulation (SCS) for chronic neuropathic pain. The field’s scope includes, but is not limited to, deep brain stimulation for movement disorders, epilepsy, or psychiatric disorders; peripheral nerve stimulation for headache or localized pain and sacral neuromoduation for pelvic organ motility disorders; esophageal, gastric or intestinal stimulation for gastroparesis, GERD, or dysmotility; vagus nerve stimulation for epilepsy or severe psychiatric disorders; carotid artery stimulation for hypertension, and SCS for ischemic disorders such as angina and peripheral vascular disease. Some of these interventions may be off-label or investigational in the U.S. but available in other parts of the world. Here, I will focus on neurosurgical procedures, although specifically trained anesthesiologists or other specialists employ a number of neuromodulation interventions. Some interventions not detailed here, such as transcranial magnetic stimulation (approved in the U.S. for medically refractory depression) are completely non-invasive and do not require surgical skills, while others (such as percutaneous posterior tibial nerve stimulation to control symptoms of overactive bladder) are minimally invasive.
Spinal Cord Stimulation
Spinal cord stimulation is the most common mode of neuromodulation. Its main indication is severe neuropathic pain that persists or recurs after technically successful spinal decompression surgery; a state known as failed back surgery syndrome. One favorable indication is complex regional pain syndrome, a chronic condition of severe pain, edema, skin changes and impaired limb function after a traumatic or iatrogenic cause. Randomized controlled trials in severe refractory neuropathic pain states, including the above, but also in painful diabetic polyneuropathy, confirm the effectiveness. Indications extend to all diagnoses of neuropathic pain of peripheral origin.
An SCS implant has stimulating electrodes implanted in the epidural space, an electrical pulse generator (IPG), implanted in the lower abdominal or gluteal region, and conducting wires connecting the electrodes to the IPG. Patients control the stimulator with a wireless remote.
The neurophysiologic mechanisms of action of SCS are not completely understood but explanations suggest an increasing GABA release coupled with glutamate suppression in the central nervous system.[1]
Patients considered for SCS usually have had chronic pain more than six months. Candidacy is determined through screening their medical and psychological health and ability to manage treatment. Since neuromodulation can reduce symptoms but does not cure the underlying cause, treatment should be undertaken as part of a healthcare team approach that provides supportive, long-term care for the patient’s underlying condition.
SCS patients first undergo several days’ trial stimulation with an external IPG (worn near the belt). With satisfactory pain relief, a permanent implant is offered. After incision healing, a device company representative or team member adjusts stimulation parameters for maximum relief.
Studies show more than 60 percent of suitable candidates who try SCS have pain lowered 50 – 70 percent, a degree that allows many to resume more day-to-day activities and enjoy a better quality of life. [2, 3]
Deep Brain Stimulation
Deep brain stimulation (DBS) delivers electrical impulses to specific brain areas to treat motor symptoms of disorders such as Parkinson’s disease, essential tremor, and dystonia. DBS was extended to control symptoms in medically refractory epilepsy, chronic pain such as central pain syndrome (off-label in the U.S.), obsessive compulsive disorder, Tourette syndrome, and major depressive disorder (investigational). DBS is also studied as a potential therapy for anorexia, obesity, and memory disorders.
During brain surgery, thin electrical leads are placed deep in the brain through small holes drilled through the skull. These leads will deliver low-voltage electrical current to a particular brain region to modify neural activity. An IPG is implanted under the collarbone. An extension wire is passed under the skin, along the neck and behind the ear, to connect the battery to the leads. Specific stimulation parameters are set for each patient.
DBS was developed after Parkinson’s disease symptoms lessened during brain surgery when electrical stimulation was used as a test. Earlier treatments, thalamotomy and pallidotomy, surgically destroyed discrete parts of the brain. Once it became possible to deliver electrical stimulation continuously through an implanted device, DBS became the preferred treatment. DBS does not permanently destroy brain tissue, is adjustable, and has been shown to be at least equally effective.
Up to 28 percent of Parkinson’s patients whose symptoms are not adequately controlled by medication alone may be good candidates for DBS. [4] Although it is not a cure, DBS can prolong the benefits of medication, allowing patients to reduce medication doses and limit side effects.
Peripheral Nerve Stimulation
Peripheral nerve stimulation (PNS) to relieve neuropathic pain adapts SCS technology. Occipital nerve stimulation used for occipital neuralgia now helps patients with chronic intractable migraine, cluster headache and hemicranias continua. Some practitioners also apply this therapy to atypical facial pain refractory to medications. Usually wire-type SCS leads are implanted subcutaneously along the distribution of a nerve, where their electrode contacts deliver stimulation from an SCS IPG. Recent clinical results have seemed to support the expectation of some clinicians that applying PNS to a combination of the occipital nerves and nerves that supply the face might result in a better outcome. [5, 6] (A partial convergence of these two systems occurs at the trigeminocervical complex.)
Vagus Nerve Stimulation
Vagus nerve stimulation (VNS) is an adjunctive treatment for certain types of intractable epilepsy and some serious psychiatric disorders. A VNS implant has two curled electrodes designed to wrap around the vagus nerve, a wire (lead), and an IPG under the clavicle. The afferent vagal fibers connect to the nucleus of the solitary tract that in turn projects connections to other locations in the central nervous system. Little is understood about exactly how VNS modulates mood and controls seizures, but proposed mechanisms include alteration of norepinephrine release by projections of solitary tract to the locus coeruleus, elevated levels of inhibitory GABA related to vagal stimulation and inhibition of aberrant cortical activity by reticular system activation. [7] VNS is also approved as an adjunctive therapy for medically refractory depression. VNS is being investigated in inflammatory diseases such as rheumatoid arthritis, asthma, and other conditions. External devices under development could widen the pool of patients who might benefit, and lower the expense.
Closed Loop Stimulation
Closed loop stimulation is a responsive treatment currently available for adults with medically refractory epilepsy. A neurostimulator implanted in the skull carries one or two leads that extend to the focal points of the seizures. Unlike VNS and DBS, which administer continuous stimulation, a closed-loop system only delivers stimulation when it detects the beginnings of seizure activity, and functions much like a pacemaker stops abnormal heart rhythms. Such stimulation either reduces the risk of having a seizure altogether or stops seizures from spreading to other parts of the brain.
The system lets doctors transfer recorded information for detailed computer analysis. This way, a clinician can observe device function, and fine-tune stimulation programs if necessary.
Intrathecal Drug Delivery Pumps
Intrathecal drug pumps deliver medications directly into the space between the spinal cord and protective sheath around it. Medications such as baclofenmorphine, or ziconotide may be delivered this way to minimize side effects from higher oral or intravenous doses. Other drugs that remain unlicensed can be used with informed patient consent. These are bupivacaine, clonidine, hydromorphone and fentanyl.
Intrathecal morphine was first used for cancer pain in the 1980s but is now widely used for severe non-cancer pain in patients with normal life expectancy. Much smaller doses are required because the drug does not have to escape metabolism and cross the blood brain barrier before reaching its site of action. Intrathecal pain medication delivery may be used for mechanical pain, a mixture of pain types, pain of multiple areas, or cancer pain.
Baclofen has been the most widely used spasticity drug since 1971. However, when taken orally it crosses the blood brain barrier poorly so high blood levels are required. This often results in unpleasant side effects and limits efficacy. Intrathecal baclofen was first reported in 1984. It achieves better concentration in the cerebrospinal fluid, effectively controls spasticity due to spinal cord injury or diseases such as multiple sclerosis, and can also be effective in spasticity of cerebral origin (brain injury, stroke, hypoxia).
Intrathecal baclofen was found to reduce central neurogenic pain; reports since the 1990s mention its effectiveness in some neuropathic pain and in augmenting SCS.
Motor Cortex Stimulation
Motor cortex stimulation by means of brain surface electrodes was introduced in 1991 and has been investigated to treat the pain suffered by some stroke victims and by people with damage to the trigeminal nerve. These are conditions for which very little else is available.
What medical specialties use neuromodulation?
Neuromodulation therapy encompasses multidisciplinary pain management groups that may include a primary care physician, neurologist, pain management anesthesiologist, physiatrist, and a surgeon (i.e. neurosurgeon, orthopedic surgeon, urologist etc.) Implantation of spinal cord stimulators can be done by a pain management physician after training in anesthesia, PM&R, or neurology. However, only neurosurgeons and orthopedic surgeons place paddle-type SCS leads that require laminectomy. New technology allows placement of paddle-type leads without laminectomy and is done by non-spinal surgeons. Pain-management-trained anesthesiologists, in addition to neurosurgeons, may implant intrathecal drug delivery pumps. Peripheral nerve stimulator implants can be done by physiatrists, neurosurgeons, urologists, colorectal surgeons, urogynecologists (sacral nerve stimulators), and otolaryingologists (vagal nerve stimulators). Intracranial implant procedures are only done by neurosurgeons. Many procedures are performed by multiple specialties including cardiologists, vascular surgeons and gastroenterologists.
The Neuromodulation Appropriateness Consensus Committee (NACC) encourages the adoption of best practice guidelines recommending that those who perform the trials and implantation are not only specifically trained but have regular experience with the neuromodulation technique. [11]
Benefits of Neuromodulation
Neuromodulation therapies improve peoples’ lives. They provide an alternative to long-term drug therapy for the symptomatic relief of persistent or chronic conditions, which is particularly important when existing drugs are simply ineffective or become problematic for long-term use due to tolerance development, addiction, adverse side effects or toxicity.
Despite their technological complexity, several studies indicate that for some patients, early use of neuromodulation technologies may be more cost effective at controlling certain conditions overall than medical or surgical management approaches, particularly when accounting for the specter of drug dependence or difficult-to-tolerate side effects of systemic medications. Examples include SCS to treat neuropathic pain and intrathecal baclofen for severe spasticity.
Where can you find more information?
Since neuromodulation therapy is an evolving field, practitioners disseminate information about neuromodulation indications and interventions in periodically updated practice guidelines, scientific literature reviews, device registries or publication databases like WikiStim, and peer-reviewed results of randomized controlled clinical trials, case series, and multicenter studies. Recently an entry summarizing the therapies was added to Wikipedia, with an extensive bibliography.
You may visit websites for the International Neuromodulation Society (INS); its official journal, Neuromodulation: Technology at the Neural Interface; and the North American Neuromodulation Society.
Social media connections: Residents and Fellows Section of the North American INS chapter, and Facebook and Twitter accounts for the INS (@IntlNeuromod).
What do you think? Join the discussion below.
References
1. Shimoji, K., et al., [Electrical management of intractable pain]. Masui, 1971. 20(5): p. 444-7.
2. Buvanendran, A. and T.J. Lubenow, Efficacy of transverse tripolar spinal cord stimulator for the relief of chronic low back pain from failed back surgery. Pain Physician, 2008. 11(3): p. 333-8.
3. Taylor, R.S., J.P. Van Buyten, and E. Buchser, Spinal cord stimulation for chronic back and leg pain and failed back surgery syndrome: a systematic review and analysis of prognostic factors. Spine (Phila Pa 1976), 2005. 30(1): p. 152-60.
4. Okun, M.S. and K.D. Foote, Parkinson’s disease DBS: what, when, who and why? The time has come to tailor DBS targets.Expert Rev Neurother, 2010. 10(12): p. 1847-57.
5. Reed, K.L., et al., Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches: initial experience. Cephalalgia, 2010. 30(3): p. 260-71.
6. Slavin, K.V. and C. Wess, Trigeminal branch stimulation for intractable neuropathic pain: technical note.Neuromodulation, 2005. 8(1): p. 7-13.
7. Ghanem, T. and S.V. Early, Vagal nerve stimulator implantation: an otolaryngologist’s perspective. Otolaryngol Head Neck Surg, 2006. 135(1): p. 46-51.
8. Anderson, W.S., et al., Implantation of a responsive neurostimulator device in patients with refractory epilepsy.Neurosurg Focus, 2008. 25(3): p. E12.
9. Gigante, P.R. and R.R. Goodman, Alternative surgical approaches in epilepsy. Curr Neurol Neurosci Rep, 2011. 11(4): p. 404-8.
10. Morrell, M.J., Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology, 2011. 77(13): p. 1295-304.
11. Deer T.R., et al. The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.Neuromodulation. 2014 Aug. 17(6):515-50; discussion 550.

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Shannon Hann, MD, is a third-year medical resident at Thomas Jefferson University Hospital Department of Neurosurgery in Philadelphia and webmaster of the North American Neuromodulation Society’s Residents and Fellows Committee. Simon Thomson, MBBS, is president of the International Neuromodulatio... Shannon Hann, MD, is a third-year medical resident at Thomas Jefferson University Hospital Department of Neurosurgery in Philadelphia and webmaster of...