A Brief History of Neuromodulation

Electricity, mainly from electric fish, was used for thousands of years to treat pain and other conditions. After it became possible to store and to control electricity in the mid -18th century its popularity increased enormously, both as quackery and for serious applications such as numbing the pain during dental operations. The modern era of neuromodulation began in the early 1960s, first with deep brain stimulation which was soon followed (in 1967) by spinal cord stimulation, both for otherwise intractable pain. The gradual realisation that pain was the result of complex dynamic processes in the nervous system and not simply the result of activity in a hard-wired system was greatly enhanced by the publication of the Gate Theory in 1965. As damage to the nervous system can itself cause chronic pain, there began a gradual move away from destructive surgical treatments such as cutting nerves and towards reversible, modulatory treatments: neuromodulation.

The applications of therapeutic electrical stimulation are very diverse and new applications are being developed. The treatment of refractory chronic pain (resistant to usual control) is the commonest indication, particularly neuropathic pain (pain generated by damaged nervous system) but also in some cases ischaemic pain (pain due to lack of oxygenated blood flow to muscles). Spinal cord stimulation (SCS) is the commonest modality and its use is well established in treatment of neuropathic pain. In addition it is used in the treatment of ischaemic pain such as angina and chronic critical limb ischaemia, visceral pain such as after chronic pancreatitis and pelvic pain disorders.

Beginning in the mid-2010s, new waveforms and SCS settings evolved, such as high frequency or burst modes of stimulation that can provide pain relief without conscious awareness of simulation, in lieu of tingling sensations of paresthesia provided by traditional SCS.

With newer SCS waveforms, a new understanding of mechanisms of action and neural dose emerged. Devices that can deliver multiple simultaneous waveforms are thought to engage multiple mechanisms of pain relief via dorsal columns. In the newer mechanistic understanding, inhibitory segmental interneurons affect the wide dynamic range neurons, or direct activation of inhibitory neurons within the dorsal horn or even activation of glial cells. A concept of neural dose emerged to identify the dose of electrical charge needed.

Also beginning in the mid-2010s, SCS systems that target other structures became available, widening the types or locations of pain that could be treated. One SCS system targets a different part of the spinal column, the dorsal root ganglion, and has shown promise for treatment of some difficult-to-treat extremity pain. Another neurostimulator system specifically for chronic mechanical (non-neuropathic) back pain became available in 2020 that directly stimulates the nerves of the lumbar multifidus muscle in order to restore muscle activation and increase stability of the lower spine, improving symptoms over time.

In the early 2020s, studies explored pain relief from more-lateral SCS stimulation fields. In 2021 it was reported that shaping the electrical field could activate a natural neurological mechanism of lateral or surround inhibition to produce fast-onset sub-perception SCS. In 2022 study results were presented of adjusting stimulation fields to preferentially target dorsal horn dendrites, which are a key site for initial pain processing, rather than axons.

Meanwhile, in 2019, closed-loop SCS was introduced to detect the effect of the stimulation on the targeted nerves, in the form of evoked compound action potentials. Sensing this feedback enables automatic stimulation adjustment for steady treatment regardless of movement, posture, or coughing that might otherwise cause a momentary dip or surge in stimulation.

As deep brain stimulation for pain declined in the 1980s it began to be used to treat motor symptoms of movement disorders such as Parkinson’s disease. This application has grown rapidly with continued research and technological developments. As with relief of chronic pain, the treatment is credited with improving function and quality of life in patients who are appropriate candidates and respond to therapy.

Peripheral nerve stimulation for pain relief in neuropathic pain or chronic migraine and chronic cluster headache also gained increasing attention. Intractable epilepsy has been treated variously with deep brain stimulation, cerebellar cortex stimulation and vagal nerve stimulation. Vagal nerve stimulation was also observed to have a mood elevating effect and received regulatory approval to be used to treat depression.

Vagus nerve stimulation that stimulates part of the autonomic nervous system gained further interest starting in the 2010s to address autoimmune inflammatory diseases such as rheumatoid arthritis, with these methods sometimes being termed by some as “bioelectronic medicine”. A handheld vagus nerve stimulation device received Emergency Use Authorization from the U.S. FDA in 2020 for use in asthmatics experiencing difficulty breathing associated with COVID-19.

Neuromodulation treatment for certain types of heart failure and hypertension also became possible in the 2010s with regulatory approvals for a neurostimulator that stimulates the baroreceptors in the heart.

The use of deep brain stimulation to treat severe intractable depression, obsessive compulsive disorder and Alzheimer’s disease is being actively explored. There are some limited studies into deep brain stimulation to potentially treat intractable obesity, addiction, or chronic pain.

Motor cortex stimulation by means of brain surface electrodes was introduced in 1991 to potentially 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.

Overcoming incontinence or retention, both urinary and faecal, by means of electrical nerve stimulation is not new, but in recent years the techniques have improved and this application is receiving a great deal of attention, and is likely to become more available. Sacral nerve stimulation and posterior tibial nerve stimulation are established treatments available to variable degrees within advanced healthcare systems.

Chronic visceral pain, chest, abdominal and pelvic, is common. Refractory angina pectoris, chronic pancreatitis, and chronic pelvic pain are continuing areas of research. Pain that has been associated with cancer and its treatment is another growing area as more and more patients survive their cancer but live with their post-cancer-therapy neuropathic and visceral pain.

The technology supporting the implantable devices used for neuromodulation has steadily improved over the last several decades. As the hardware becomes smaller and more user friendly for both doctor and patient, it seems likely that the use of neuromodulation will grow. Up to a 100,000 units were already implanted annually by the 2020s, but this represents only a small proportion of those people who could benefit. However, the penetration of neuromodulation has not matched the growth of existing indications nor the developments of new indications. Patient access to these therapies is restricted by combinations of lack of awareness by patient and referrer, lack of skilled implant sites and lack of healthcare resources.

The idea that opioid drugs such as morphine, fentanyl or hydromorphone might be more effective if injected directly into the spinal fluid (i.e intrathecally) was first tested with morphine in 1977 and the first internalised infusion pump was implanted in 1981. Such pumps have evolved from patient-activated bolus devices and constant infusion systems to complex programmable units. Intrathecal morphine was first used for cancer pain but is now used for severe pain of non-cancer origin in patients with normal life expectancy. In some health economies the use of intrathecal drug delivery in non-cancer pain is being withdrawn pending clinical trials demonstrating clinical and cost effectiveness. Such randomized controlled trials are difficult to do and expensive, so it is possible that we will see the demise of this therapy.

Several other drugs are also suitable for this approach and are often used in combination. Much smaller doses are required because the drug escapes first-pass metabolism and more easily crosses the blood-brain barrier to reach site of action. There are fewer side effects but the wide individual variation in both responsiveness and side effects can mean that this treatment is unsuitable for some patients. Many tens of thousands of patients do benefit from this treatment, particularly those with mechanical pain, a mixture of pain types, pain in multiple areas and cancer pain.

Baclofen has been the most widely used drug in treating spasticity since its introduction in 1971. However, when taken orally it crosses the blood-brain barrier very poorly so that high blood levels of the drug are required to achieve satisfactory levels in the cerebrospinal fluid and nervous system. This often results in unpleasant side effects and lack of efficacy. The direct intrathecal administration of baclofen was first reported in 1984 and, dose for dose, achieves a concentration in the cerebrospinal fluid approximately 400 times higher. Intrathecal baclofen has proved to be extremely effective in controlling spasticity due to spinal cord injury and diseases such as multiple sclerosis and can also be effective in spasticity of cerebral origin (brain injury, stroke, hypoxia). In addition to its often dramatic effect against spasticity, intrathecal baclofen was found to have an analgesic effect; reports have appeared since the early 1990s regarding its effectiveness in some cases of neuropathic pain and its use in augmenting spinal cord stimulation.

Ziconotide, a non-opioid agent specific for continuous intrathecal delivery, was marketed to treat severe pain beginning in 2005. It can only be given intrathecally from precision infusion devices and needs to be managed carefully.

Like stimulation devices, intrathecal drug delivery pumps are becoming smaller (or the same overall size can have a bigger reservoir) and more user friendly. The bigger the reservoir the longer the interval between refills but the stability of the drug in solution over time has to be considered.  Similar to neurostimulation, microdosing appears to offer same benefits but at a far lower daily dose.

Neuromodulation treatments for patients whose chronic conditions cause suffering and disability often involve invasive technologies, but can bring considerable relief and improvement in select patients, sometimes after other measures have failed. In most cases neuromodulation therapy no longer is a treatment of last resort, and its earlier implementation may even modify the trajectory of some chronic conditions.

The application of functional electrical stimulation (FES) had its origins in the management of spinal injury and post-stroke care. A number of external and implantable devices have been designed and manufactured to restore useful function in an otherwise intact nervous system. Cochlear implants for hearing are one of the first technological examples. Later, visual prosthetic systems emerged that provide some visual perception. Small clinical studies starting in the early 2000s have investigated cortical sensing allowing people with severe paralysis to use a brain-machine interface to sense motor intentions and operate a computer cursor or robotic arm.

Broad applications range from a method of enhancing physical rehabilitation after such an injury to the restoration of upper and lower limb function, bladder, bowel, sexual function and chest ventilation after severe spinal cord injury. Research work first reported in 2014 has been using specifically programmed spinal cord stimulators to augment restoration of mobility after complete spinal cord injury.

Neuromodulation is a broad field for medicine and even non-medical applications. It offers as much promise as other technologies such as stem cell and gene therapies but entered physicians' armamentarium for many indications sooner. The hopes of using computer technology interfacing with human tissue to restore, augment, or replace abnormal function is a reality but has further to go. It is to be hoped that the availability of these clinical and cost-effective treatments will continue to increase.

Dr. Simon Thomson, MBBS, FRCA, FIPP, FFPMRCA
Consultant in Pain & Neuromodulation, Mid & South Essex University Hospitals NHS FT, U.K.

INS offices previously held:
Emeritus Director at Large 2017-2020
Immediate Past President 2015-2017
President, International Neuromodulation Society, 2009-2015
President-elect 2007-2009
Secretary INS 2003-2007
INS board member 2001-2003
Founding President of Neuromodulation Society of UK and Ireland 2000-2003

Aug. 3, 2022

(Please note: This information should not be used as a substitute for medical treatment and advice. Always consult a medical professional about any health-related questions or concerns.)

Last Updated on Wednesday, August 03, 2022 09:59 AM