Neuromodulation

Neuromodulation is "the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body". It is carried out to normalize – or modulate – nervous tissue function. Neuromodulation is an evolving therapy that can involve a range of electromagnetic stimuli such as a magnetic field (rTMS), an electric current, or a drug instilled directly in the subdural space (intrathecal drug delivery). Emerging applications involve targeted introduction of genes or gene regulators and light (optogenetics), and by 2014, these had been at minimum demonstrated in mammalian models, or first-in-human data had been acquired.[1] The most clinical experience has been with electrical stimulation.

Neuromodulation, whether electrical or magnetic, employs the body's natural biological response by stimulating nerve cell activity that can influence populations of nerves by releasing transmitters, such as dopamine, or other chemical messengers such as the peptide Substance P, that can modulate the excitability and firing patterns of neural circuits. There may also be more direct electrophysiological effects on neural membranes as the mechanism of action of electrical interaction with neural elements. The end effect is a "normalization" of a neural network function from its perturbed state. Presumed mechanisms of action for neurostimulation include depolarizing blockade, stochastic normalization of neural firing, axonal blockade, reduction of neural firing keratosis, and suppression of neural network oscillations.[2] Although the exact mechanisms of neurostimulation are not known, the empirical effectiveness has led to considerable application clinically.

Existing and emerging neuromodulation treatments also include application in medication-resistant epilepsy,[3] chronic head pain conditions, and functional therapy ranging from bladder and bowel or respiratory control to improvement of sensory deficits, such as hearing (cochlear implants and auditory brainstem implants) and vision (retinal implants).[4] Technical improvements include a trend toward minimally invasive (or noninvasive) systems; as well as smaller, more sophisticated devices that may have automated feedback control,[5] and conditional compatibility with magnetic resonance imaging.[6][7]

Neuromodulation therapy has been investigated for other chronic conditions, such as Alzheimer's disease,[8][9] depression, chronic pain,[10][11] and as an adjunctive treatment in recovery from stroke.[12][13]

Invasive electrical neuromodulation methods

Electrical stimulation using implantable devices came into modern usage in the 1980s and its techniques and applications have continued to develop and expand.[14] These are methods where an operation is required to position an electrode. The stimulator, with the battery, similar to a pacemaker, may also be implanted, or may remain outside the body.

In general, neuromodulation systems deliver electrical currents and typically consist of the following components: An epidural, subdural or parenchymal electrode placed via minimally invasive needle techniques (so-called percutaneous leads) or an open surgical exposure to the target (surgical "paddle" or "grid" electrodes), or stereotactic implants for the central nervous system, and an implanted pulse generator (IPG). Depending on the distance from the electrode access point an extension cable may also be added into the system. The IPG can have either a non-rechargeable battery needing replacement every 2–5 years (depending on stimulation parameters) or a rechargeable battery that is replenished via an external inductive charging system.

Although most systems operate via delivery of a constant train of stimulation, there is now the advent of so-called "feed-forward" stimulation where the device's activation is contingent on a physiological event, such as an epileptic seizure. In this circumstance, the device is activated and delivers a desynchronizing pulse to the cortical area that is undergoing an epileptic seizure. This concept of feed-forward stimulation will likely become more prevalent as physiological markers of targeted diseases and neural disorders are discovered and verified.[15] The on-demand stimulation may contribute to longer battery life, if sensing and signal-processing demands of the system are sufficiently power-efficient. New electrode designs could yield more efficient and precise stimulation, requiring less current and minimizing unwanted side-stimulation. In addition, to overcome the challenge of preventing lead migration in areas of the body that are subject to motion such as turning and bending, researchers are exploring developing small stimulation systems that are recharged wirelessly rather than through an electrical lead.[16]

Spinal cord stimulation

Main article: Spinal cord stimulation

Spinal cord stimulation is a form of invasive neuromodulation therapy in common use since the 1980s. Its principal use is as a reversible, non-pharmacological therapy for chronic pain management that delivers mild electrical pulses to the spinal cord.[17] In patients who experience pain reduction of 50 percent or more during a temporary trial, a permanent implant may be offered in which, as with a cardiac pacemaker, an implantable pulse generator about the size of a stopwatch is placed under the skin on the trunk. It delivers mild impulses along slender electrical leads leading to small electrical contacts, about the size of a grain of rice, at the area of the spine to be stimulated.[18]

Stimulation is typically in the 20–200 Hz range, though a novel class of stimulation parameters are now emerging that employ a 10 kHz stimulation train as well as 500 Hz "burst stimulation". Kilohertz stimulation trains have been applied to both the spinal cord proper as well as the dorsal root ganglion in humans. All forms of spinal cord stimulation have been shown to have varying degrees of efficacy to address a variety of pharmacoresistant neuropathic or mixed (neuropathic and noiciceptive) pain syndromes such as post-laminectomy syndrome, low back pain, complex regional pain syndrome, peripheral neuropathy, peripheral vascular disease and angina.[19]

The general process for spinal cord stimulation involves a temporary trailing of appropriate patients with an external pulse generator attached to epidural electrodes located in the lower thoracic spinal cord. The electrodes are placed either via a minimally invasive needle technique (so-called percutaneous leads) or an open surgical exposure (surgical "paddle" electrodes).

Patient selection is key, and candidates should pass rigorous psychological screening as well as a medical workup to assure that their pain syndrome is truly medication-resistant.[19] After recuperating from the implant procedure, the patient will return to have the system turned on and programmed. Depending on the system, the program may elicit a tingling sensation that covers most of the painful area, replacing some of the painful sensations with more of a gentle massaging sensation, although other more recent systems do not create a tingling sensation. The patient is sent home with a handheld remote controller to turn the system off or on or switch between pre-set stimulation parameters, and can follow up to adjust the parameters.

Deep brain stimulation

Main article: Deep brain stimulation

Another invasive neuromodulation treatment developed in the 1980s is deep brain stimulation, which may be used to help limit symptoms of movement disorder in Parkinson's disease, dystonia, or essential tremor.[20] Deep brain stimulation was approved by the U.S. Food and Drug Administration in 1997 for essential tremor, in 2002 for Parkinson's disease, and received a humanitarian device exemption from the FDA in 2003 for motor symptoms of dystonia.[21] It was approved in 2010 in Europe for the treatment of certain types of severe epilepsy.[22] DBS also has shown promise, although still in research, for medically intractable psychiatric syndromes of depression, obsessive compulsive disorders, intractable rage, dementia, and morbid obesity. It has also shown promise for Tourette syndrome, torticollis, and tardive dyskinesia. DBS therapy, unlike spinal cord stimulation, has a variety of central nervous system targets, depending on the target pathology. For Parkinson's disease central nervous system targets include the subthalamic nucleus, globus pallidus interna, and the ventral intermidus nucleus of the thalamus. Dystonias are often treated by implants targeting globus pallidus interna, or less often, parts of the ventral thalamic group. The anterior thalamus is the target for epilepsy.[23][24][21]

DBS research targets include, but are not limited to the following areas: Cg25 for depression, the anterior limb of the internal capsule for depression as well as obsessive compulsive disorder (OCD), centromedian/parafasicularis, centromedian thalamic nuclei and the subthalamic nucleus for OCD, anorexia and Tourette syndrome, the nucleus accumbens and ventral striatum have also been assayed for depression and pain.[24][21]

Other invasive electrical methods

Non-invasive electrical methods

These methods use external electrodes to apply a current to the body in order to change the functioning of the nervous system.

Methods include:

Non-invasive magnetic methods

Magnetic methods of neuromodulation are normally non-invasive: no surgery is required to allow a magnetic field to enter the body because the magnetic permeability of tissue is similar to that of air. In other words: magnetic fields penetrate the body very easily.

The two main techniques are highly related in that both use changes in magnetic field strength to induce electric fields and ionic currents in the body. There are however differences in approach and hardware. In rTMS the stimulation has a high amplitude (0.5–3 tesla), a low complexity and anatomical specificity is reached through a highly focal magnetic field. In tPEMF the stimulation has a low amplitude (0.01–500 millitesla), a high complexity and anatomical specificity is reached through the specific frequency content of the signal.[27]

Invasive chemical methods

Chemical neuromodulation is always invasive, because a drug is delivered in a highly specific location of the body. The non-invasive variant is traditional pharmacotherapy, e.g. swallowing a tablet.

History

Electrical stimulation of the nervous system has a long and complex history. Earlier practitioners of deep brain stimulation in the latter half of the 20th century (Delgado, Heath, Hosbuchi. See Hariz et al. for historical review[28]) were limited by the technology available. Heath, in the 1950s, stimulated subcortical areas and made detailed observations of behavioral changes. A new understanding of pain perception was ushered in in 1965, with the Gate Theory of Wall and Melzack.[29] Although now considered oversimplified, the theory held that pain transmissions from small nerve fibers can be overridden, or the gate "closed", by competing transmissions along the wider touch nerve fibers. Building on that concept, in 1967, the first dorsal column stimulator for pain control was demonstrated by Dr. Norm Shealy at Western Reserve Medical School, using a design adapted by Tom Mortimer, a graduate student at Case Institute of Technology, from cardiac nerve stimulators by Medtronic, Inc., where he had a professional acquaintance who shared the circuit diagram. In 1973, Hosbuchi reported alleviating the denervation facial pain of anesthesia dolorosa through ongoing electrical stimulation of the somatosensory thalamus, marking the start of the age of deep brain stimulation.[14]: 13–16 [30][31]

Despite the limited clinical experience in these decades, that era is remarkable for the demonstration of the role technology has in neuromodulation, and there are some case reports of deep brain stimulation for a variety of problems; real or perceived. Delgado hinted at the power of neuromodulation with his implants in the bovine septal region and the ability of electrical stimulation to blunt or alter behavior. Further attempts at this "behavioral modification" in humans were difficult and seldom reliable, and contributed to the overall lack of progress in central nervous system neuromodulation from that era. Attempts at intractable pain syndromes were met with more success, but again hampered by the quality of technology. In particular, the so-called DBS "zero" electrode, (consisting of a contact loop on its end) had an unacceptable failure rate and revisions were fraught with more risk than benefit. Overall, attempts at using electrical stimulation for "behavioral modification" were difficult and seldom reliable, slowing development of DBS. Attempts at addressing intractable pain syndromes with DBS were met with more success, but again hampered by the quality of technology. A number of physicians who hoped to address hitherto intractable problems sought development of more specialized equipment; for instance, in the 1960s, Wall's colleague Bill Sweet recruited engineer Roger Avery to make an implantable peripheral nerve stimulator. Avery started the Avery Company, which made a number of implantable stimulators. Shortly before his retirement in 1983, he submitted data requested by the FDA, which had begun to regulate medical devices following a 1977 meeting on the topic, regarding DBS for chronic pain. Medtronic and Neuromed also made deep brain stimulators at the time, but reportedly felt a complex safety and efficacy clinical trial in patients who were difficult to evaluate would be too costly for the size of the potential patient base, so did not submit clinical data on DBS for chronic pain to the FDA, and that indication was de-approved.[14]: 13–16 [30][31]

However, near this time in France and elsewhere, DBS was investigated as a substitute for lesioning of brain nuclei to control motor symptoms of movement disorders such as Parkinson's disease, and by the mid-1990s, this reversible, non-destructive stimulation therapy had become the primary application of DBS in appropriate patients, to slow progression of movement impairment from the disease and reduce side effects from long-term, escalating medication use.[32]

In parallel to the development of neuromodulation systems to address motor impairment, cochlear implants were the first neuromodulation system to reach a broad commercial stage to address a functional deficit; they provide sound perception in users who are hearing-impaired due to missing or damaged sensory cells (cilia) in the inner ear. The approach to electrical stimulation used in cochlear implants was soon modified by one manufacturer, Boston Scientific Corporation, for design of electrical leads to be used in spinal cord stimulation treatment of chronic pain conditions.[14]: 13–16 

Relationship to electroceuticals

In 2012, the global pharmaceutical company GlaxoSmithKline announced an initiative in bioelectric medicine in which the autonomic nervous system's impact on the immune system and inflammatory disease might be treated through electrical stimulation rather than pharmaceutical agents. The company's first investment in 2013 involved a small startup company, SetPoint Medical, which was developing neurostimulators to address inflammatory autoimmune disorders such as rheumatoid arthritis.[33][34][35]

Ultimately, the electroceuticals quest aims to find the electro-neural signature of disease and at a cellular level, in real time, play back the more normal electro-signature to help maintain the neural signature in the normal state. Unlike preceding neuromodulation therapy methods, the approach would not involve electrical leads stimulating large nerves or spinal cords or brain centers. It might involve methods that are emerging within the neuromodulation family of therapies, such as optogenetics or some new nanotechnology. Disease states and conditions that have been discussed as targets for future electroceutical therapy include diabetes, infertility, obesity, rheumatoid arthritis, and autoimmune disorders.[36]

See also

References

  1. ^ "International Neuromodulation Society home page". Retrieved 1 October 2013.
  2. ^ Karas PJ, Mikell CB, Christian E, Liker MA, Sheth SA (November 2013). "Deep brain stimulation: a mechanistic and clinical update". Neurosurgical Focus. 35 (5): E1. doi:10.3171/2013.9.focus13383. PMID 24175861. S2CID 26756883.
  3. ^ Al-Otaibi FA, Hamani C, Lozano AM (October 2011). "Neuromodulation in epilepsy". Neurosurgery. 69 (4): 957–79, discussion 979. doi:10.1227/NEU.0b013e31822b30cd. PMID 21716154. S2CID 23473956.
  4. ^ Krames, Elliot S.; Peckham, P. Hunter; Rezai, Ali R., eds. (2009). Neuromodulation, Vol. 1-2. Academic Press. p. 274. ISBN 9780123742483.
  5. ^ Wu C, Sharan AD (2013). "Neurostimulation for the treatment of epilepsy: a review of current surgical interventions". Neuromodulation. 16 (1): 10–24, discussion 24. doi:10.1111/j.1525-1403.2012.00501.x. PMID 22947069. S2CID 1711587.
  6. ^ "Precision™ Plus Spinal Cord Stimulator System Receives CE Mark Approval as MRI Conditional". Paris, France: Boston Scientific Corporation. August 28, 2012. Retrieved September 27, 2013.
  7. ^ "Medtronic Introduces the First and Only Neurostimulation Systems for Chronic Pain Designed for Full-Body MRI Safety". Minneapolis, MN: Medtronic, Inc. August 6, 2013. Archived from the original on 2019-04-17. Retrieved September 27, 2013.
  8. ^ Clinical trial number NCT01559220 for "Deep Brain Stimulation for the Treatment of Alzheimer's Disease." at ClinicalTrials.gov
  9. ^ Clinical trial number NCT01608061 for "Functional Neuromodulation Ltd. ADvance DBS-f in Patients With Mild Probable Alzheimer's Disease." at ClinicalTrials.gov
  10. ^ Kortekaas R, van Nierop LE, Baas VG, Konopka KH, Harbers M, van der Hoeven JH, et al. (2013). "A novel magnetic stimulator increases experimental pain tolerance in healthy volunteers - a double-blind sham-controlled crossover study". PLOS ONE. 8 (4): e61926. Bibcode:2013PLoSO...861926K. doi:10.1371/journal.pone.0061926. PMC 3631254. PMID 23620795.
  11. ^ Shupak NM, Prato FS, Thomas AW (June 2004). "Human exposure to a specific pulsed magnetic field: effects on thermal sensory and pain thresholds". Neuroscience Letters. 363 (2): 157–62. doi:10.1016/j.neulet.2004.03.069. PMID 15172106. S2CID 41394936.
  12. ^ Matsumura Y, Hirayama T, Yamamoto T (2013). "Comparison between pharmacologic evaluation and repetitive transcranial magnetic stimulation-induced analgesia in poststroke pain patients". Neuromodulation. 16 (4): 349–54, discussion 354. doi:10.1111/ner.12019. PMID 23311356. S2CID 206204986.
  13. ^ a b Feng WW, Bowden MG, Kautz S (2013). "Review of transcranial direct current stimulation in poststroke recovery". Topics in Stroke Rehabilitation. 20 (1): 68–77. doi:10.1310/tsr2001-68. PMID 23340073. S2CID 39688758.
  14. ^ a b c d Krames, Elliot S.; Peckham, P. Hunter; Rezai, Ali R., eds. (2009). Neuromodulation, Vol. 1-2. Academic Press. pp. 1–1200. ISBN 9780123742483.
  15. ^ Sun FT, Morrell MJ, Wharen RE (January 2008). "Responsive cortical stimulation for the treatment of epilepsy". Neurotherapeutics. 5 (1): 68–74. doi:10.1016/j.nurt.2007.10.069. PMC 5084128. PMID 18164485.
  16. ^ Deer TR, Krames E, Mekhail N, Pope J, Leong M, Stanton-Hicks M, et al. (August 2014). "The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states. Neuromodulation Appropriateness Consensus Committee". Neuromodulation. 17 (6): 599–615, discussion 615. doi:10.1111/ner.12204. PMID 25112892. S2CID 20959524.
  17. ^ Mekhail NA, Cheng J, Narouze S, Kapural L, Mekhail MN, Deer T (2010). "Clinical applications of neurostimulation: forty years later". Pain Practice. 10 (2): 103–12. doi:10.1111/j.1533-2500.2009.00341.x. PMID 20070547. S2CID 24008740.
  18. ^ Bailey, Madeleine (May 14, 2013). "A remote control turns off my spine". The Express. London, UK.
  19. ^ a b Deer TR, Mekhail N, Provenzano D, Pope J, Krames E, Leong M, et al. (August 2014). "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. 17 (6): 515–50, discussion 550. doi:10.1111/ner.12208. PMID 25112889. S2CID 16831609.
  20. ^ Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, et al. (February 2011). "Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues". Archives of Neurology. 68 (2): 165. doi:10.1001/archneurol.2010.260. PMC 4523130. PMID 20937936.
  21. ^ a b c Williams NR, Okun MS (November 2013). "Deep brain stimulation (DBS) at the interface of neurology and psychiatry". The Journal of Clinical Investigation. 123 (11): 4546–56. doi:10.1172/JCI68341. PMC 3809784. PMID 24177464.
  22. ^ "Medtronic Receives European CE Mark Approval for Deep Brain Stimulation Therapy for Refractory Epilepsy Further Clinical Study Required for Application to U.S. Food and Drug Administration" (Press release). 16 September 2010. Archived from the original on 17 April 2019. Retrieved 2014-10-12.
  23. ^ Wilner A (22 April 2010). "Thalamic Stimulation: New Approach to Treatment of Epilepsy". Medscape Neurology. Retrieved Oct 13, 2014.
  24. ^ a b Lozano AM, Lipsman N (February 2013). "Probing and regulating dysfunctional circuits using deep brain stimulation". Neuron. 77 (3): 406–24. doi:10.1016/j.neuron.2013.01.020. PMID 23395370.
  25. ^ George MS, Nahas Z, Borckardt JJ, Anderson B, Burns C, Kose S, Short EB (January 2007). "Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders". Expert Review of Neurotherapeutics. 7 (1): 63–74. doi:10.1586/14737175.7.1.63. PMID 17187498. S2CID 35340441.
  26. ^ "Premarket Approval (PMA) Inspire II Upper Airway Stimulation System". U.S. Food and Drug Administration. April 30, 2014.
  27. ^ Whissell PD, Persinger MA (December 2007). "Emerging synergisms between drugs and physiologically-patterned weak magnetic fields: implications for neuropharmacology and the human population in the twenty-first century". Current Neuropharmacology. 5 (4): 278–88. doi:10.2174/157015907782793603. PMC 2644491. PMID 19305744.
  28. ^ Hariz MI, Blomstedt P, Zrinzo L (August 2010). "Deep brain stimulation between 1947 and 1987: the untold story". Neurosurgical Focus. 29 (2): E1. doi:10.3171/2010.4.FOCUS10106. PMID 20672911. S2CID 28313693.
  29. ^ Wall PD, Melzack R (1996). The challenge of pain (2nd ed.). New York: Penguin Books. pp. 61–69. ISBN 0-14-025670-9.
  30. ^ a b Lozano AM, Gildenberg PL, Tasker RR, eds. (2009). Textbook of Stereotactic and Functional Neurosurgery. Vol. 1. pp. 16–20.
  31. ^ a b Bittar RG, Kar-Purkayastha I, Owen SL, Bear RE, Green A, Wang S, Aziz TZ (June 2005). "Deep brain stimulation for pain relief: a meta-analysis". Journal of Clinical Neuroscience. 12 (5): 515–9. doi:10.1016/j.jocn.2004.10.005. PMID 15993077. S2CID 24246117.
  32. ^ Benabid AL, Chabardes S, Torres N, Piallat B, Krack P, Fraix V, Pollak P (2009). "Functional neurosurgery for movement disorders: a historical perspective". Neurotherapy: Progress in Restorative Neuroscience and Neurology. Progress in Brain Research. Vol. 175. pp. 379–91. doi:10.1016/S0079-6123(09)17525-8. ISBN 9780123745118. PMID 19660668.
  33. ^ Cookson C (31 July 2012). "Healthcare: Into the cortex Scientific advances on the brain promise to transform the pharmaceutical industry". Financial Times. London. Retrieved 11 October 2014.
  34. ^ Famm K, Litt B, Tracey KJ, Boyden ES, Slaoui M (April 2013). "Drug discovery: a jump-start for electroceuticals". Nature. 496 (7444): 159–61. Bibcode:2013Natur.496..159F. doi:10.1038/496159a. PMC 4179459. PMID 23579662.
  35. ^ Carroll J (10 April 2013). "GlaxoSmithKline stakes a pioneering effort to launch 'electroceutical' R&D". Fierce Biotech. Retrieved 11 October 2014.
  36. ^ Birmingham K, Gradinaru V, Anikeeva P, Grill WM, Pikov V, McLaughlin B, et al. (June 2014). "Bioelectronic medicines: a research roadmap" (PDF). Nature Reviews. Drug Discovery. 13 (6) (published 30 May 2014): 399–400. doi:10.1038/nrd4351. PMID 24875080. S2CID 20061363.

Further reading

External links

Categories