Deep brain stimulation

Deep brain stimulation

DBS-probes shown in X-ray of the skull (white areas around maxilla and mandible represent metal dentures and are unrelated to DBS devices)
MeSH D046690
MedlinePlus 007453

Deep brain stimulation (DBS) is a neurosurgical procedure involving the implantation of a medical device called a neurostimulator (sometimes referred to as a 'brain pacemaker'), which sends electrical impulses, through implanted electrodes, to specific targets in the brain (brain nuclei) for the treatment of movement and neuropsychiatric disorders. DBS in select brain regions has provided therapeutic benefits for otherwise-treatment-resistant disorders such as Parkinson's disease, essential tremor, dystonia, chronic pain, major depression and obsessive–compulsive disorder (OCD).[1] Despite the long history of DBS,[2] its underlying principles and mechanisms are still not clear.[3][4] DBS directly changes brain activity in a controlled manner, its effects are reversible (unlike those of lesioning techniques), and it is one of only a few neurosurgical methods that allow blinded studies.[1]

The Food and Drug Administration (FDA) approved DBS as a treatment for essential tremor and Parkinson's disease in 1997,[5] dystonia in 2003,[6] and OCD in 2009.[7] DBS is also used in research studies to treat chronic pain, PTSD,[8][9] and has been used to treat various affective disorders, including major depression; none of these applications of DBS have yet been FDA-approved. While DBS has proven to be effective for some patients, potential for serious complications and side effects exists.

Drawing of DBS electrodes deep in the brain.(Side view)

Components and placement

The deep brain stimulation system consists of three components: the implanted pulse generator (IPG), the lead, and an extension. The IPG is a battery-powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain that interferes with neural activity at the target site. The lead is a coiled wire insulated in polyurethane with four platinum-iridium electrodes and is placed in one or two different nuclei of the brain. The lead is connected to the IPG by an extension, an insulated wire that runs below the skin, from the head, down the side of the neck, behind the ear to the IPG, which is placed subcutaneously below the clavicle or, in some cases, the abdomen.[10] The IPG can be calibrated by a neurologist, nurse, or trained technician to optimize symptom suppression and control side-effects.[11]

DBS leads are placed in the brain according to the type of symptoms to be addressed. For non-Parkinsonian essential tremor, the lead is placed in the ventrointermediate nucleus (VIM) of the thalamus; for dystonia and symptoms associated with Parkinson's disease (rigidity, bradykinesia/akinesia, and tremor), the lead may be placed in either the globus pallidus internus or the subthalamic nucleus; for OCD and depression to the nucleus accumbens; for incessant pain to the posterior thalamic region or periaqueductal gray; for Parkinson plus patients to two nuclei simultaneously, subthalamic nucleus and tegmental nucleus of pons, with the use of two pulse generators; and for epilepsy treatment to the anterior thalamic nucleus.[12]

All three components are surgically implanted inside the body. Lead implantation may take place under local anesthesia or with the patient under general anesthesia ("asleep DBS") such as for dystonia. A hole about 14 mm in diameter is drilled in the skull and the probe electrode is inserted stereotactically. During the awake procedure with local anesthesia, feedback from the patient is used to determine the optimal placement of the permanent electrode. During the asleep procedure, intraoperative MRI guidance is used for direct visualization of brain tissue and device.[13] The installation of the IPG and extension leads occurs under general anesthesia.[14] The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.

Applications

Parkinson's disease

Insertion of electrode during surgery using a stereotactic frame

The use of DBS as a treatment for Parkinson's disease dates from 1987. [15] Parkinson's disease is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia, and postural instability.[16] DBS does not cure Parkinson's, but it can help manage some of its symptoms and subsequently improve the patient’s quality of life.[17] At present, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications, or whose medications have severe side-effects.[10] Its direct effect on the physiology of brain cells and neurotransmitters is currently debated, but by sending high frequency electrical impulses into specific areas of the brain it can mitigate symptoms[18] and directly diminish the side-effects induced by Parkinson's medications,[19] allowing a decrease in medications, or making medication regimen more tolerable.

There are few sites in the brain that can be targeted to achieve differing results, so each patient must be assessed individually, and a site will be chosen based on their needs. Traditionally, the two most common sites are the subthalamic nucleus (STN) and the globus pallidus interna (GPi), but other sites, such as the caudal zona incerta and the pallidofugal fibers medial to the STN, are being evaluated and show promise.[20]

In the United States DBS is approved by the Food and Drug Administration for the treatment of Parkinson's.[21] DBS carries the risks of major surgery, with a complication rate related to the experience of the surgical team. The major complications include hemorrhage (1–2%) and infection (3–5%).[22]

Chronic pain

Stimulation of the periaqueductal gray and periventricular gray for nociceptive pain, and the internal capsule, ventral posterolateral nucleus, and ventral posteromedial nucleus for neuropathic pain has produced impressive results with some patients, but results vary and appropriate patient selection is important. One study[23] of seventeen patients with intractable cancer pain found that thirteen were virtually pain-free and only four required opioid analgesics on release from hospital after the intervention. Most ultimately did resort to opioids, usually in the last few weeks of life.[24] DBS has also been applied for phantom limb pain.[25]

Major depression and obsessive-compulsive disorder

Deep brain stimulation has been used in a small number of clinical trials to treat patients suffering from a severe form of treatment-resistant depression (TRD).[26] A number of neuroanatomical targets have been utilised for deep brain stimulation for TRD including the subgenual cingulate gyrus, posterior gyrus rectus,[27] nucleus accumbens,[28] ventral capsule/ventral striatum, inferior thalamic peduncle, and the lateral habenula.[26] A recently proposed target of DBS intervention in depression is the superolateral branch of the medial forebrain bundle (slMFB), its stimulation lead to surprisingly rapid antidepressant effects in very treatment resistant patients.[29]

The small patient numbers in the early trials of deep brain stimulation for TRD currently limit the selection of an optimal neuroanatomical target.[26] There is insufficient evidence to support DBS as a therapeutic modality for depression; however, the procedure may be an effective treatment modality in the future.[30] In fact, beneficial results have been documented in the neurosurgical literature, including a few instances in which deeply depressed patients were provided with portable stimulators for self-treatment.[31][32][33]

A systematic review of DBS for treatment-resistant depression and obsessive–compulsive disorder identified 23 cases—9 for OCD, 7 for treatment-resistant depression, and 1 for both. It was found that "about half the patients did show dramatic improvement" and that adverse events were "generally trivial" given the younger psychiatric patient population than with movements disorders.[34] The first randomized controlled study of DBS for the treatment of treatment resistant depression targeting the ventral capsule/ventral striatum area did not demonstrate a significant difference in response rates between the active and sham groups at the end of a 16-week study.[35]

DBS for treatment-resistant depression can be as effective as antidepressants, with good response and remission rates, but adverse effects and safety must be more fully evaluated. Common side-effects include "wound infection, perioperative headache, and worsening/irritable mood [and] increased suicidality".[36]

Tourette syndrome

Deep brain stimulation has been used experimentally in treating adults with severe Tourette syndrome that does not respond to conventional treatment. Despite widely publicized early successes, DBS remains a highly experimental procedure for the treatment of Tourette's, and more study is needed to determine whether long-term benefits outweigh the risks.[37][38][39][40] The procedure is well tolerated, but complications include "short battery life, abrupt symptom worsening upon cessation of stimulation, hypomanic or manic conversion, and the significant time and effort involved in optimizing stimulation parameters".[41] As of 2006, there were five reports in patients with TS; all experienced reduction in tics and the disappearance of obsessive-compulsive behaviors.[41]

The procedure is invasive and expensive, and requires long-term expert care. Benefits for severe Tourette's are not conclusive, considering less robust effects of this surgery seen in the Netherlands. Tourette's is more common in pediatric populations, tending to remit in adulthood, so in general this would not be a recommended procedure for use on children. Because diagnosis of Tourette's is made based on a history of symptoms rather than analysis of neurological activity, it may not always be clear how to apply DBS for a particular patient. Due to concern over the use of DBS in Tourette syndrome, the Tourette Association of America convened a group of experts to develop recommendations guiding the use and potential clinical trials of DBS for TS.[42]

Robertson reported that DBS had been used on 55 adults by 2011, remained an experimental treatment at that time, and recommended that the procedure "should only be conducted by experienced functional neurosurgeons operating in centres which also have a dedicated Tourette syndrome clinic".[38] According to Malone et al (2006), "Only patients with severe, debilitating, and treatment-refractory illness should be considered; while those with severe personality disorders and substance abuse problems should be excluded."[41] Du et al (2010) say that "As an invasive therapy, DBS is currently only advisable for severely affected, treatment-refractory TS adults".[39] Singer (2011) says that "pending determination of patient selection criteria and the outcome of carefully controlled clinical trials, a cautious approach is recommended".[37] Viswanathan et al (2012) say that DBS should be used in patients with "severe functional impairment that can not be managed medically".[43]

Other clinical applications

Results of DBS in dystonia patients, where positive effects often appear gradually over a period of weeks to months, indicate a role of functional reorganization in at least some cases.[44] The procedure has been tested for effectiveness in people with epilepsy that is resistant to medication.[45] DBS may reduce or eliminate epileptic seizures with programmed or responsive stimulation.

DBS of the septal areas of persons with schizophrenia have resulted in enhanced alertness, cooperation, and euphoria.[46] Persons with narcolepsy and complex-partial seizures also reported euphoria and sexual thoughts from self-elicited DBS of the septal nuclei.[32]

Orgasmic ecstasy was reported with the electrical stimulation of the brain with depth electrodes in the left hippocampusat 3mA, and the right hippocampus at 1 mA.[47]

Adverse effects

While DBS is helpful for some patients, there is also the potential for neuropsychiatric side-effects, including apathy, hallucinations, hypersexuality, cognitive dysfunction, depression, and euphoria. However, these may be temporary and related to correct placement of electrodes and calibration of the stimulator, so these side effects are potentially reversible.[48]

Because the brain can shift slightly during surgery, there is the possibility that the electrodes can become displaced or dislodged from the specific location. This may cause more profound complications such as personality changes, but electrode misplacement is relatively easy to identify using CT. There may also be complications of surgery, such as bleeding within the brain. After surgery, swelling of the brain tissue, mild disorientation, and sleepiness are normal. After 2–4 weeks, there is a follow-up to remove sutures, turn on the neurostimulator, and program it.

As with all surgery there is the risk of infection and bleeding during and after a surgery. The foreign object placed may be rejected by the body or calcification of the implant might take place.

Mechanisms

The exact mechanism of action of DBS is not known.[49] There are a variety of classes of hypotheses to explain the mechanisms of DBS:[50][51]

  1. Depolarization blockade: Electrical currents block the neuronal output at or near the electrode site.
  2. Synaptic inhibition: This causes an indirect regulation of the neuronal output by activating axon terminals with synaptic connections to neurons near the stimulating electrode.
  3. De-synchronization of abnormal oscillatory activity of neurons.
  4. Antidromic activation either activating/blockading distant neurons or blockading slow axons.[4]

Deep brain stimulation represents an advance on previous treatments which involved pallidotomy (i.e., surgical ablation of the globus pallidus) or thalamotomy (i.e., surgical ablation of the thalamus).[52] Instead, a thin lead with multiple electrodes is implanted in the globus pallidus, nucleus ventralis intermedius thalami (Vim) or the subthalamic nucleus and electric pulses are used therapeutically. The lead from the implant is extended to the neurostimulator under the skin in the chest area.

See also

Notes

  1. 1 2 Kringelbach ML, Jenkinson N, Owen SL, Aziz TZ (2007). "Translational principles of deep brain stimulation". Nature Reviews Neuroscience. 8 (8): 623–635. PMID 17637800. doi:10.1038/nrn2196.
  2. ↑ Gildenberg PL (2005). "Evolution of neuromodulation". Stereotact Funct Neurosurg. 83 (2–3): 71–79. PMID 16006778. doi:10.1159/000086865.
  3. ↑ Hammond C.; Ammari R; Bioulac B; Garcia L (2008). "Latest view on the mechanism of action of deep brain stimulation". Mov Disord. 23 (15): 2111–21. PMID 18785230. doi:10.1002/mds.22120.
  4. 1 2 García MR, Pearlmutter BA, Wellstead PE, Middleton RH (2013). "A Slow Axon Antidromic Blockade Hypothesis for Tremor Reduction via Deep Brain Stimulation". PLoS ONE. 8 (9): e73456. PMC 3774723 Freely accessible. PMID 24066049. doi:10.1371/journal.pone.0073456.
  5. ↑ "Press Announcements - FDA approves brain implant to help reduce Parkinson’s disease and essential tremor symptoms". FDA. Retrieved May 23, 2016. The first device, Medtronic’s Activa Deep Brain Stimulation Therapy System, was approved in 1997 for tremor associated with essential tremor and Parkinson’s disease.
  6. ↑ 'Brain pacemaker' treats dystonia. KNBC TV, April 22, 2003. Retrieved October 18, 2006.
  7. ↑ "FDA Approves Humanitarian Device Exemption for Deep Brain Stimulator for Severe Obsessive-Compulsive Disorder". FDA.
  8. ↑ Langevin, J. P.; De Salles, A. A.; Kosoyan, H. P.; Krahl, S. E. (2010). "Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model". J Psychiatr Res. 44 (16): 1241–5. PMID 20537659. doi:10.1016/j.jpsychires.2010.04.022.
  9. ↑ Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder / 2013
  10. 1 2 National Institute of Neurological Disorders and Stroke. Deep brain stimulation for Parkinson's Disease information page. Retrieved November 23, 2006.
  11. ↑ Volkmann J, Herzog J, Kopper F, Deuschl G (2002). "Introduction to the programming of deep brain stimulators". Mov Disord. 17: S181–187. PMID 11948775. doi:10.1002/mds.10162.
  12. ↑ Deep brain stimulation. Surgery Encyclopedia. Retrieved January 25, 2007.
  13. ↑ Starr PA, Martin AJ, Ostrem JL, Talke P, Levesque N, Larson PS (Mar 2010). "Subthalamic nucleus deep brain stimulator placement using high-field interventional magnetic resonance imaging and a skull-mounted aiming device: technique and application accuracy". J Neurosurg. 112 (3): 479–90. PMC 2866526 Freely accessible. PMID 19681683. doi:10.3171/2009.6.JNS081161.
  14. ↑ Deep Brain Stimulation, Department of Neurological Surgery, University of Pittsburgh. Retrieved May 13, 2008.
  15. ↑ "The History of Deep Brain Stimulation". The Parkinson's Appeal for Deep Brain Stimulation.
  16. ↑ Ropper (2005), p. 916
  17. ↑ Kleiner-Fisman G, Herzog J, Fisman DN, et al. (Jun 2006). "Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes". Mov Disord. 21 (Suppl 14): S290–304. PMID 16892449. doi:10.1002/mds.20962.
  18. ↑ Moro E, Lang AE (Nov 2006). "Criteria for deep-brain stimulation in Parkinson's disease: review and analysis". Expert Review of Neurotherapeutics. 6 (11): 1695–705. PMID 17144783. doi:10.1586/14737175.6.11.1695.
  19. ↑ Apetauerova D, Ryan RK, Ro SI, Arle J, et al. (Aug 2006). "End of day dyskinesia in advanced Parkinson's disease can be eliminated by bilateral subthalamic nucleus or globus pallidus deep brain stimulation". Movement Disorders. 21 (8): 1277–9. PMID 16637040. doi:10.1002/mds.20896.
  20. ↑ Plaha P, Ben-Shlomo Y, Patel NK, Gill SS (July 2006). "Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism". Brain. 129 (Pt 7): 1732–47. PMID 16720681. doi:10.1093/brain/awl127.
  21. ↑ U.S. Department of Health and Human Services. FDA approves implanted brain stimulator to control tremors. Retrieved February 10, 2015.
  22. ↑ Doshi PK (April 2011). "Long-term surgical and hardware-related complications of deep brain stimulation". Stereotact Funct Neurosurg. 89 (2): 89–95. PMID 21293168. doi:10.1159/000323372.
  23. ↑ Young RF & Brechner T. Electrical stimulation of the brain for relief of intractable pain due to cancer. Cancer. 1986;57:1266–72. doi:10.1002/1097-0142(19860315)57:6<1266::aid-cncr2820570634>3.0.co;2-q. PMID 3484665.
  24. ↑ Johnson MI, Oxberry SG & Robb K. Stimulation-induced analgesia. In: Sykes N, Bennett MI & Yuan C-S. Clinical pain management: Cancer pain. 2nd ed. London: Hodder Arnold; 2008. ISBN 978-0-340-94007-5. p. 235–250.
  25. ↑ Kringelbach Morten L, et al. (2007). "Deep brain stimulation for chronic pain investigated with magnetoencephalography". NeuroReport. 18 (3): 223–228. PMID 17314661. doi:10.1097/wnr.0b013e328010dc3d.
  26. 1 2 3 Anderson RJ, Frye MA, Abulseoud OA, et al. (September 2012). "Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action". Neurosci Biobehav Rev. 36 (8): 1920–33. PMID 22721950. doi:10.1016/j.neubiorev.2012.06.001.
  27. ↑ Accolla, Ettore A.; Aust, Sabine; Merkl, Angela; Schneider, Gerd-Helde; Kühn, Andrea A.; Bajbouj, Malek; Draganski, Bogdan (2016). "Deep brain stimulation of the posterior gyrus rectus region for treatment resistant depression". Journal of Affective Disorders. 194: 33–37. PMID 26802505. doi:10.1016/j.jad.2016.01.022.
  28. ↑ Schlaepfer, TE; et al. (2008). "Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression". Neuropsychopharmacology. 33 (2): 368–77. PMID 17429407. doi:10.1038/sj.npp.1301408.
  29. ↑ Schlaepfer, TE; et al. (2013). "Rapid effects of deep brain stimulation for treatment-resistant major depression". Biological Psychiatry. 73 (12): 1204–12. PMID 23562618. doi:10.1016/j.biopsych.2013.01.034.
  30. ↑ Curr Opin Psychiatry. 2009 May;22(3):306–11
  31. ↑ Delgado, Jose (1986). Physical Control of the Mind: Toward a Psychocivilized Society. New York: Harper and Row.
  32. 1 2 Faria, MA (2013). "Violence, mental illness, and the brain – A brief history of psychosurgery: Part 3 – From deep brain stimulation to amygdalotomy for violence behavior, seizures, and pathological aggression in humans". Surg Neurol Int. 4 (1): 91. PMC 3740620 Freely accessible. PMID 23956934. doi:10.4103/2152-7806.115162.
  33. ↑ Robison, RA; Taghva A; Liu CY; Apuzzo ML (2012). "Surgery of the mind, mood and conscious state: an idea in evolution". World Neurosurg. 77 (5–6): 662–686. PMID 22446082. doi:10.1016/j.wneu.2012.03.005.
  34. ↑ Lakhan SE, Callaway H (Mar 2010). "Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review". BMC Research Notes. 3 (1): 60. PMC 2838907 Freely accessible. PMID 20202203. doi:10.1186/1756-0500-3-60.
  35. ↑ Dougherty, Darin D.; Rezai, Ali R.; Carpenter, Linda L.; Howland, Robert H.; Bhati, Mahendra T.; o'Reardon, John P.; Eskandar, Emad N.; Baltuch, Gordon H.; Machado, Andre D.; Kondziolka, Douglas; Cusin, Cristina; Evans, Karleyton C.; Price, Lawrence H.; Jacobs, Karen; Pandya, Mayur; Denko, Timothey; Tyrka, Audrey R.; Brelje, Tim; Deckersbach, Thilo; Kubu, Cynthia; Malone, Donald A. (2015). "A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression". Biological Psychiatry. 78 (4): 240–248. PMID 25726497. doi:10.1016/j.biopsych.2014.11.023.
  36. ↑ Moreines JL, McClintock SM, Holtzheimer PE (Jan 2011). "Neuropsychologic effects of neuromodulation techniques for treatment-resistant depression: a review". Brain Stimul. 4 (1): 17–27. PMC 3023999 Freely accessible. PMID 21255751. doi:10.1016/j.brs.2010.01.005.
  37. 1 2 Singer HS (March 2005). "Tourette syndrome and other tic disorders". Handb Clin Neurol. 100: 641–57. PMID 21496613. doi:10.1016/B978-0-444-52014-2.00046-X. Also see Singer HS (March 2005). "Tourette's syndrome: from behaviour to biology". Lancet Neurol. 4 (3): 149–59. PMID 15721825. doi:10.1016/S1474-4422(05)01012-4.
  38. 1 2 Robertson MM (February 2011). "Gilles de la Tourette syndrome: the complexities of phenotype and treatment". Br J Hosp Med. 72 (2): 100–7. PMID 21378617. doi:10.12968/hmed.2011.72.2.100.
  39. 1 2 Du JC, Chiu TF, Lee KM, et al. (Oct 2010). "Tourette syndrome in children: an updated review". Pediatr Neonatol. 51 (5): 255–64. PMID 20951354. doi:10.1016/S1875-9572(10)60050-2.
  40. ↑ Tourette Syndrome Association. Statement: Deep Brain Stimulation and Tourette Syndrome. Retrieved November 22, 2005.
  41. 1 2 3 Malone DA Jr; Pandya MM (2006). "Behavioral neurosurgery". Adv Neurol. 99: 241–7. PMID 16536372.
  42. ↑ Mink JW, Walkup J, Frey KA, et al. (November 2006). "Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome". Mov Disord. 21 (11): 1831–8. PMID 16991144. doi:10.1002/mds.21039.
  43. ↑ Viswanathan A, Jimenez-Shahed J, Baizabal Carvallo JF, Jankovic J (2012). "Deep brain stimulation for Tourette syndrome: target selection". Stereotact Funct Neurosurg. 90 (4): 213–24. PMID 22699684. doi:10.1159/000337776.
  44. ↑ Krauss JK (2002). "Deep brain stimulation for dystonia in adults. Overview and developments". Stereotactic and Functional Neurosurgery. 78 (3–4): 168–182. PMID 12652041. doi:10.1159/000068963.
  45. ↑ Wu C, Sharan AD (Jan–Feb 2013). "Neurostimulation for the treatment of epilepsy: a review of current surgical interventions". Neuromodulation. 16 (1): 10–24. PMID 22947069. doi:10.1111/j.1525-1403.2012.00501.x.
  46. ↑ Heath, R. G. (1972). "Pleasure and brain activity in man. Deep and surface electroencephalograms during orgasm". The Journal of Nervous and Mental Disease. 154 (1): 3–18. ISSN 0022-3018. PMID 5007439. doi:10.1097/00005053-197201000-00002.
  47. ↑ Surbeck W, Bouthillier A, Nguyen DK. "Bilateral cortical representation of orgasmic ecstasy localized by depth electrodes". Epilepsy Behav Case Rep. 1: 62–5. PMC 4150648 Freely accessible. PMID 25667829. doi:10.1016/j.ebcr.2013.03.002.
  48. ↑ Burn DJ, Tröster AI (September 2004). "Neuropsychiatric complications of medical and surgical therapies for Parkinson's disease". J Geriatr Psychiatry Neurol. 17 (3): 172–80. PMID 15312281. doi:10.1177/0891988704267466.
  49. ↑ Mogilner A.Y.; Benabid A.L.; Rezai A.R. (2004). "Chronic Therapeutic Brain Stimulation: History, Current Clinical Indications, and Future Prospects". In Markov, Marko; Paul J. Rosch. Bioelectromagnetic medicine. New York, N.Y: Marcel Dekker. pp. 133–51. ISBN 0-8247-4700-3.
  50. ↑ McIntyre CC, Thakor NV (2002). "Uncovering the mechanisms of deep brain stimulation for Parkinson's disease through functional imaging, neural recording, and neural modeling". Crit Rev Biomed Eng. 30 (4–6): 249–81. PMID 12739751. doi:10.1615/critrevbiomedeng.v30.i456.20.
  51. ↑ Herrington TM, Cheng JJ, Eskandar EM (2016). "Mechanisms of deep brain stimulation". J. Neurophysiol. 115 (4–6): 19–38. PMC 4760496 Freely accessible. PMID 26510756. doi:10.1152/jn.00281.2015.
  52. ↑ Machado A, Rezai AR, Kopell BH, Gross RE, Sharan AD, Benabid AL (June 2006). "Deep brain stimulation for Parkinson's disease: surgical technique and perioperative management". Mov. Disord. 21 (Suppl 14): S247–58. PMID 16810722. doi:10.1002/mds.20959.

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