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Deep-brain stimulation

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Deep-brain stimulation

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 therapeutic benefits for otherwise-treatment-resistant movement and affective disorders such as Parkinson's disease, essential tremor, dystonia, and chronic pain.[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 .

The Food and Drug Administration (FDA) approved DBS as a treatment for essential tremor in 1997, for Parkinson's disease in 2002,[5] and dystonia in 2003.[6] DBS is also used in research studies to treat chronic pain and has been used to treat various affective disorders, including major depression; neither of these applications of DBS have yet been FDA-approved. While DBS has proven helpful for some patients, 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.[7] The IPG can be calibrated by a neurologist, nurse, or trained technician to optimize symptom suppression and control side-effects.[8]

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 or the subthalamic nucleus.[9]

All three components are surgically implanted inside the body. Lead and extension implantation may take place under local anesthesia or with the patient under general anesthesia ("asleep DBS"). A hole about 14 mm in diameter is drilled in the skull and the electrode is inserted. During the awake procedure with local anesthesia, feedback from the patient is used to determine optimal placement. During the asleep procedure, intraoperative MRI guidance is used for direct visualization of brain tissue and device.[10] The installation of the IPG and lead occurs under general anesthesia.[11] The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.


It has been shown in thalamic slices from mice[12] that DBS causes nearby astrocytes to release adenosine triphosphate (ATP), a precursor to adenosine (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus causing an inhibitory effect that mimics ablation or "lesioning". Other observations, however, have called this inhibition hypothesis into question. We have the apparent contradiction that lesioning of the globus pallidus externus (GPe) can produce Parkinsonism while DBS of the GPe can reverse Parkinsonian symptoms.[13]


Parkinson's disease

Parkinson's disease is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia, and postural instability.[14] DBS does not cure Parkinson's, but it can help manage some of its symptoms and subsequently improve the patient’s quality of life.[15] At present, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications, or whose medications have severe side-effects.[7] 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[16] and/or directly diminish the side-effects induced by Parkinsonian medications,[17] 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.[18]

Research is being conducted as of 2007 to predict the onset of tremors before they occur by monitoring activity in the subthalamic nucleus. The goal is to provide stimulating pulses only when they are needed, to stop any tremors occurring before they start.[19]

DBS is approved in the United States by the Food and Drug Administration for the treatment of Parkinson's.[5] 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%).[20]

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[21] 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.[22] DBS has also been applied for phantom limb pain.[23]

Major depression

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).[24] A number of neuroanatomical targets have been utilised for deep brain stimulation for TRD including the subgenual cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, inferior thalamic peduncle, and the lateral habenula.[24] The small patient numbers in the early trials of deep brain stimulation for TRD currently limit the selection of an optimum neuroanatomical target.[24] 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.[25]

A systematic review of DBS for treatment-resistant depression and obsessive–compulsive disorder identified 23 cases—nine for OCD, seven for treatment-resistant depression, and one for both. It 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.[26]

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".[27]

Recently, results of Deep Brain Stimulation to the Medial forebrain bundle have been published.[28] The findings suggest that bilateral stimulation of the supero-lateral branch of the medial forebrain bundle may significantly reduce symptoms in treatment-resistant major depressive disorder. Onset of antidepressant efficacy was rapid (days), and a higher proportion of the population responded at lower stimulation intensities than observed in previous studies.

Tourette syndrome

Further information: Treatment of 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.[29][30][31][32] 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".[33] As of 2006, there were five reports in patients with TS; all experienced reduction in tics and the disappearance of obsessive-compulsive behaviors.[33]

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 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.[34]

Robertson reports that DBS had been used on 55 adults as of 2011, remains an experimental treatment,[30] and "should only be conducted by experienced functional neurosurgeons operating in centres which also have a dedicated Tourette syndrome clinic".[30] 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."[33] Du et al (2010) say that "As an invasive therapy, DBS is currently only advisable for severely affected, treatment-refractory TS adults".[31] Singer (2011) says that "pending determination of patient selection criteria and the outcome of carefully controlled clinical trials, a cautious approach is recommended".[29] Viswanathan A et al (2012) say that DBS should be used in patients with "severe functional impairment that can not be managed medically".[35]

Other clinical applications

Alzheimer's: A 2010 study on the impact of DBS on Alzheimer's disease "suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients."[36][37]

Trauma/coma: In August 2007, Nature reported that scientists in the US had stimulated a 38-year-old man who had been in a minimally conscious state for six years using DBS.[38] The patient initially had increased arousal and sustained eye-opening, as well as rapid bilateral head-turning to voice. After further stimulation, the previously non-verbal patient became capable of naming objects and using objects with his hands—for example, bringing a cup to his mouth. Moreover, he could swallow food and take meals by mouth, meaning that he was no longer dependent on a gastrostomy tube.[39] This result follows research carried out over 40 years, which has analyzed the effects of deep brain stimulation in the thalamus (and elsewhere) in patients with post-traumatic coma.[40][41][42] While this research has shown some potential, deep brain stimulation is not yet a reliable cure for patients in post-traumatic coma.

OCD: DBS has been used in the treatment of obsessive-compulsive disorder[43] Although the clinical efficacy is not questioned, the mechanisms by which DBS works are still debated.[44] Long-term clinical observation has shown that the mechanism is not due to a progressive lesion, given that interruption of stimulation reverses its effects.[44] DBS has not been approved as an evidence-based therapy for depression or OCD in North America.

Dystonia: 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.[45]

Epilepsy: The procedure has been tested for effectiveness in patients with severe epilepsy.[46] A review of 189 studies covering DBS as well as vagus nerve stimulation and closed-loop stimulation (responsive neurostimulator [RNS]) indicate that neurostimulation provides "another tool with which to treat the complex disease of medically refractory epilepsy."[47]

Self-injury syndrome: DBS has produced encouraging results for patients with Lesch-Nyhan syndrome in Japan, Switzerland and France and USA[48]

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.[49] A 2006 study of 99 Parkinson's patients that had undergone DBS suggested a decline in executive functions relative to patients that 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.[50]

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. 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.

See also



  • 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 ML, Jenkinson N, Owen SLF, Aziz TZ (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 0-07-141620-X

External links

  • Video: Deep brain stimulation to treat Parkinson's disease
  • Video: Deep brain stimulation therapy for Parkinson's disease
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