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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.^[1] Despite the long history of DBS,^[2] 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,^[3] and dystonia in 2003.^[4] DBS is also routinely used to treat chronic pain and has been used to treat various affective disorders, including major depression. While DBS has proven helpful for some patients, there is potential for serious complications and side effects.

Contents 1 Components and placement 2 Biochemistry 3 Applications 3.1 Parkinson's disease 3.2 Major depression 3.3 Tourette syndrome 3.4 Other clinical applications 4 Potential complications and side effects 5 See also 6 Notes 7 References 8 External links

[edit] 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.^[5] The IPG can be calibrated by a neurologist, nurse or trained technician to optimize symptom suppression and control side effects.^[6]

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 ventrointermedial 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 subthalamic nucleus.^[7]

All three components are surgically implanted inside the body. Under local anesthesia, a hole about 14 mm in diameter is drilled in the skull and the electrode is inserted, with feedback from the patient for optimal placement. The installation of the IPG and lead occurs under general anesthesia.^[8] The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.

[edit] Biochemistry

It has been shown in thalamic slices from mice^[9] 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 mimicks ablation or "lesioning".

[edit] Applications

[edit] Parkinson's disease

Parkinson's disease (also known as paralysis agitans) is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia and postural instability.^[10] DBS does not cure Parkinson's, but it can help manage some of its symptoms and subsequently improve the patient’s quality of life.^[11] At present, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications, or whose medications have severe side effects.^[5] 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^[12] and/or directly diminish the side effects induced by Parkinsonian medications,^[13] 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.^[14]

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.^[15]

DBS is approved in the United States by the Food and Drug Administration for the treatment of Parkinson's.^[3] DBS carries the risks of major surgery, with a complication rate related to the experience of the surgical team.

[edit] Major depression

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 major depression. Their symptoms had previously been resistant to medication, psychotherapy and electroconvulsive therapy.^[16]

Using brain imaging, the researchers had 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.^[16]

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.^[16]

Another hypothetically interesting site for DBS in depression is the nucleus accumbens,^[17] as that region appears to be associated with pleasure and reward mechanisms. A 2007 study reported that experimental use of deep brain stimulation of the nucleus accumbens showed promising results, with patients suffering from profound depression reporting relief from their symptoms.^[18]

[edit] Tourette syndrome

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.^[19] 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".^[20] 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."^[20] 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.^[21]

[edit] Other clinical applications

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.^[22] 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 he was no longer dependent on a gastrostomy tube.^[23]

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.^[24][25][26] While this research has shown some potential, deep brain stimulation is not yet a reliable cure for patients in post-traumatic coma.

DBS has been used in the treatment of obsessive-compulsive disorder^[27] and phantom limb pain.^[28] Although the clinical efficacy is not questioned, the mechanisms by which DBS works are still debated.^[29] Long-term clinical observation has shown that the mechanism is not due to a progressive lesion, given that interruption of stimulation reverses its effects.^[29] 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.^[30] The procedure is being tested for effectiveness in patients with severe epilepsy.^[31]

DBS has been tried for patients with Lesch-Nyhan syndrome in Japan, Switzerland and France.^{[citation needed]}

[edit] 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.^[32] 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.^[33]

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.

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.

[edit] See also

• Neurosurgery
• Stereotactic surgery
• Psychosurgery
• Neuroprosthetics
• Brain implant
• Vagus nerve stimulation

[edit] Notes

[edit] References

• 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
• Bekar L, Libionka W, Tian G, Xu Q, Torres A, Wang X, Lovatt D, Williams E, Takano T, Schnermann J, Bakos R, Nedergaard M (2008). "Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor". Nature Medicine, v.14, n.1, pp.75–80.
• 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 007141620X

[edit] External links

• Deep brain stimulation for movement disorders