Deep brain stimulation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
In neurotechnology, deep brain stimulation (DBS) is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. DBS in select brain regions has provided remarkable therapeutic benefits for otherwise treatment-resistant movement and affective disorders such as chronic pain, Parkinson’s disease, tremor and dystonia . Yet, despite the long history of DBS , its underlying principles and mechanisms are still not clear. DBS directly changes brain activity in a controlled manner, its effects are reversible (unlike those of lesioning techniques) and is one of only a few neurosurgical methods that allows blinded studies.
The Food and Drug Administration (FDA) approved DBS as a treatment for essential tremor in 1997, for Parkinson's disease in 2002 , and dystonia in 2003 . DBS is also routinely used to treat chronic pain and has been used to treat various affective disorders, including clinical depression. While DBS has proven helpful for some patients (e.g., see videos ), there is potential for serious complications and side effects.
Components and placement
The deep brain stimulation system consists of three components: the implanted pulse generator (IPG), the lead, and the extension. The IPG is a battery-powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain to interfere 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 of three areas of the brain. The lead is connected to the IPG by the extension, an insulated wire that runs 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. The IPG can be calibrated by a neurologist, nurse or trained technician to optimize symptom suppression and control side effects. 
DBS leads are placed in the brain according to the type of symptoms to be addressed. For essential tremor and Parkinsonian tremors, the lead is placed in 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 or subthalamic nucleus.
All three components are surgically implanted inside the body. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.
The procedure begins with preoperative identification of the neurosurgical target with computed tomography (CT), magnetic resonance imaging (MRI) or, in earlier times, ventriculography.
During surgery, the patient is given local anesthesia and remains awake. A craniotomy is performed and a DBS lead is placed either unilaterally or bilaterally, depending on the patient's symptoms. Microelectrode recording may be used to more precisely locate the desired target within the brain. The IPG and extension are then implanted and connected to each lead.
Depending on the procedures of the medical facility, all components of the DBS system may not be implanted during a single surgery. After surgery is completed, the IPG is calibrated to maximize its effectiveness. Programming can take up to a year to achieve optimal settings.
Due to battery depletion, the IPG must be replaced—usually after three to five years, depending on the settings used. The entire unit is replaced to maintain an uncontaminated field within the body. Nevertheless, this is a minor surgical procedure involving only the shallow subclavicular pocket where the IPG resides. Remaining battery life may be reliably determined with a telemetric programmer so that arrangements can be made to replace the unit prior to battery failure.
Parkinson's disease (also known as paralysis agitans) is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia and postural instability. DBS does not cure Parkinson's, but it can help manage some of its symptoms and subsequently improve the patient’s quality of life. At present, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications, or whose medications have severe side effects. 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 and/or directly diminish the side effects induced by Parkinsonian medications, allowing a decrease in medications, or making a medication regimen more tolerable.
There are a 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 showing promise.
DBS is approved in the United States by the Food and Drug Administration for the treatment of Parkinson's. DBS carries the risks of major surgery, with a complication rate related to the experience of the surgical team.
Newer techniques, not using the stereotactic frame, have been developed and are now widely used. This helps in the accuracy of the placement and the comfort of the patient.
Researchers reported in 2005 that electrical stimulation of a small area of the frontal cortex brought about a "striking and sustained remission" in four out of six patients suffering from clinical depression, whose symptoms had previously been resistant to medication, psychotherapy and electroconvulsive therapy.
Using brain imaging, the researchers noticed that activity in the subgenual cingulate region (SCR or Brodmann area 25)—the lowest part of a band of tissue that runs along the midline of the brain—seemed to correlate with symptoms of sadness and depression. They implanted electrodes into six patients while they were locally anesthetised, but alert. While the current was switched on, four of the patients reported feeling a black cloud lifting, and became more alert and interested in their environments. The changes reversed when the current was switched off.
The effects of continuous SCR stimulation have produced sustained remission from depression in the four patients for six months. When reporting the results, the team did caution that the trial was so small that the findings must be considered only provisional.
Another hypothetically interesting site for DBS in depression is the nucleus accumbens, as that region appears to be associated with pleasure and reward mechanisms. Experimental use of deep brain stimulation has shown promising results, with patients suffering from profound depression reporting relief from their symptoms.
Deep brain stimulation has been used experimentally in treating a few patients with severe Tourette syndrome. 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 risk. 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". As of 2006, there were five published reports of DBS in patients with TS; all experienced reduction in tics and the disappearance of obsessive-compulsive behaviors. "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." There may be serious short- and long-term risks associated with DBS in persons with head and neck tics. 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 this would not generally 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 the treatment of Tourette syndrome, the Tourette Syndrome Association convened a group of experts to develop recommendations guiding the use and potential clinical trials of DBS for TS.
Other clinical applications
In August 2007, Nature reported that scientists in the US has successfully stimulated a 38-year-old man who had been in a minimally conscious state for six years using DBS.
DBS has been used in the treatment of obsessive-compulsive disorder, phantom limb pain, and cluster headaches. Although the clinical efficacy is not questioned, the mechanisms by which DBS works is still debated. Long-term clinical observation has shown that the mechanism is not due to a progressive lesion, given that interruption of stimulation reverses its effects. 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. The procedure is being tested for effectiveness in patients with severe epilepsy.
Subthalamic nucleus deep brain stimulators
Potential complications and side effects
While DBS is helpful for some patients, there is also the potential for neuropsychiatric side effects. Reports in the literature describe the possibility of apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfunction, and depression. However, these may be temporary and related to correct placement and calibration of the stimulator and so are potentially reversible. A recent trial of 99 Parkinson's patients who had undergone DBS suggested a decline in executive functions relative to patients who had not undergone DBS, accompanied by problems with word generation, attention and learning. About 9% of patients had "psychiatric events", which ranged in severity from a relapse in voyeurism to a suicide attempt. Most patients in this trial reported an improvement in their quality of life following DBS, and there was an improvement in their physical functioning.
Because the brain can shift slightly during surgery, there is the possibility that the electrodes can become displaced or dislodged. This may cause more profound complications such as personality changes, but electrode misplacement is relatively easy to identify using CT or MRI. There may also be complications of surgery, such as bleeding within the brain.
- swelling of the brain tissue is normal
- mild disorientation, sleepiness
- follow up after 2-4 weeks to remove sutures, turn on the neurostimulator and program it
- Stereotactic surgery
- Brain implant
- Vagus nerve stimulation
- ↑ Kringelbach M.L., Jenkinson N., Owen S.L.F. & Aziz T.Z. (2007) Translational principles of deep brain stimulation. Nature Reviews Neuroscience. 8:623-635. PMID 17637800.
- ↑ Gildenberg Philip L. (2005) Evolution of neuromodulation. Stereotact Funct Neurosurg, 83(2-3), 71-79. PMID 16006778.
- ↑ 3.0 3.1 U.S. Department of Health and Human Services.FDA APPROVES IMPLANTED BRAIN STIMULATOR TO CONTROL TREMORS. Retrieved October 18, 2006.
- ↑ 'Brain pacemaker' treats dystonia. KNBC TV, April 22, 2003. Retrieved October 18, 2006.
- ↑ http://www.nature.com/nrn/journal/v8/n8/suppinfo/nrn2196.html
- ↑ 6.0 6.1 National Institute of Neurological Disorders and Stroke. Deep brain stimulation for Parkinson's Disease information page. Retrieved 23 November 2006.
- ↑ Volkmann J, Herzog J, Kopper F, Deuschl G. Introduction to the programming of deep brain stimulators. Mov Disord. 2002 17, S181-187. PMID 11948775.
- ↑ Deep brain stimulation. Surgery Encyclopedia. Retrieved January 25, 2007.
- ↑ Gildenberg and Tasker (1998), Part 4, pp. 879-1217
- ↑ Ropper (2005), p. 916
- ↑ Kleiner-Fisman G, Herzog J, Fisman DN, et al. "Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes." Mov Disord. 2006 Jun;21 Suppl 14:S290-304 PMID 16892449
- ↑ Moro E, Lang AE. "Criteria for deep-brain stimulation in Parkinson's disease: review and analysis". Expert Review of Neurotherapeutics. 2006 Nov;6(11):1695-705. PMID 17144783
- ↑ Apetauerova D, Ryan RK, Ro SI, Arle J, et al. "End of day dyskinesia in advanced Parkinson's disease can be eliminated by bilateral subthalamic nucleus or globus pallidus deep brain stimulation". Movement Disorders. 2006 Aug;21(8):1277-9. PMID 16637040
- ↑ Plaha P, Ben-Shlomo Y, Patel NK, Gill SS. "Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism". Brain (2006). 129, 1732-1747 PMID 16720681
- ↑ 15.0 15.1 15.2 Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005 Mar 3;45(5):651-60. PMID 15748841.
- ↑ Schlaepfer TE, Lieb K. Deep brain stimulation for treatment of refractory depression. Lancet. 2005 Oct 22-28;366(9495):1420-2. PMID 16243078.
- ↑ Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression. Neuropsychopharmacology. 2007 Apr 11. PMID 17429407.
- ↑ Tourette Syndrome Association. Statement: Deep Brain Stimulation and Tourette Syndrome. Retrieved November 22 2005.
- ↑ 19.0 19.1 Malone DA Jr, Pandya MM. Behavioral neurosurgery. Adv Neurol. 2006;99:241-7. PMID 16536372
- ↑ Mink JW, Walkup J, Frey KA, et al. Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome. Mov Disord. 2006 Nov;21(11):1831-8. PMID 16991144
- ↑ Implant boosts activity in injured brain. Nature news (1 August 2007). Retrieved on 2007-08-01
- ↑ Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B (1999) Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet. 1999 Oct 30;354(9189):1526 PMID 10551504
- ↑ Kringelbach, Morten L. et al. (2007). "Deep brain stimulation for chronic pain investigated with magnetoencephalography". Neuroreport, 18(3), pp. 223-228.
- ↑ 24.0 24.1 Benabid AL, Wallace B, Mitrofanis J, Xia R, Piallat B, Chabardes S, Berger F. (2005) A putative generalized model of the effects and mechanism of action of high frequency electrical stimulation of the central nervous system. Acta Neurol Belg. 2005 Sep;105(3):149-57. PMID 16255153
- ↑ Krauss JK (2002). "Deep brain stimulation for dystonia in adults. Overview and developments". Stereotactic and Functional Neurosurgery. 78 (3–4): 168–182. PMID 12652041.
- ↑ Velasco F, Velasco M, Velasco AL, Jimenez F, Marquez I, Rise M. Electrical stimulation of the centromedian thalamic nucleus in control of seizures: long-term studies. Epilepsia 36: 63-71, 1995. PMID 8001511
- ↑ Burn D, Troster A (2004). "Neuropsychiatric Complications of Medical and Surgical Therapies for Parkinson's Disease". Journal of Geriatric Psychiatry and Neurology. 17 (3): 172–180. PMID 15312281.
- ↑ Smeding H, Speelman J, Koning-Haanstra M; et al. (2006). "Neuropsychological effects of bilateral STN stimulation in Parkinson disease: A controlled study". Neurology. 66 (12): 1830–1836. PMID 16801645.
- Appleby BS, Duggan PS, Regenberg A, Rabins PV (2007) Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: A meta-analysis of ten years' experience. Movement Disorders 22:1722-1728 PMID 17721929
- Fins JJ. Deep Brain Stimulation (2004) In, Encyclopedia of Bioethics, 3rd Edition. Post, SG, Editor-in-Chief. New York: MacMillan Reference. Volume 2, pp. 629-634.
- Gildenberg Philip L. and Tasker, Ronald R. (1998) Textbook of stereotactic and functional neurosurgery, McGraw-Hill Publishing.
- Gildenberg Philip L. (2005) Evolution of neuromodulation. Stereotact Funct Neurosurg, 83(2-3), 71-79. PMID 16006778
- Kringelbach M.L., Jenkinson N., Owen S.L.F. & Aziz T.Z. (2007) Translational principles of deep brain stimulation. Nature Reviews Neuroscience. 8:623-635. PMID 17637800
- McIntyre CC, Grill WM (2000) Selective microstimulation of central nervous system neurons. Annals of Biomedical Engineering 38:219-233. PMID 10784087
- McIntyre CC, Grill WM, Sherman DL, Thakor NV (2004) Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. Journal of Neurophysiology 91:1457–1469. PMID 14668299
- Ropper Allan H and Brown, Robert H. (2005) Adams and Victor's Principles of Neurology (8th Edition), McGraw-Hill Medical Publishing. ISBN 007141620X
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