Deep+Brain+Stimulation

**Introduction**
media type="youtube" key="kWAVOhl9OFk" width="436" height="248" align="right" Deep brain stimulation (DBS) is a surgical procedure that has received Food and Drug Administration (FDA) approval within the U.S. for alleviating symptoms associated with Parkinson’s disease and essential tremor. It is also being used as an experimental form of treatment for several other conditions and disorders such as: depression, Alzheimer’s disease, Tourette’s syndrome, minimally conscious state, obesity, anorexia, neuropathic pain, substance addiction, tinnitus, Huntington’s disease, among others. DBS is not recommended as a first option treatment. The procedure is most commonly recommended for late stages in movement disorders after a patient has been treated with medications. Once a patient’s quality of life has deteriorated due to impaired motor symptoms, and mood along with cognitive functioning are still in normal ranges, DBS becomes a viable treatment option. After DBS, these medication-refractory patients have been found to gain approximately eighty percent improvement in reduced tremor. In addition, improvements in both bradykinesia (slowness of movement) and rigidity are reported.

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Basal ganglia is usually the main part treated by DBS (Wicnmann and Delong 2011). Subthalamic nucleus (STN) is effective for tremor, slowness, rigidity, and dystonia, and it is treated for Parkinson's disease the most common (Mandybur and Gartner 2016). Ventral intermediate nucleus in the thalamus (Vim) is an effective area to treat for tremor, particularly essential tremor (Mandybur and Gartner 2016). Targeting the initial segment of globus pallidus is effective for tremor, slowness, ridigity, dystonia, and dyskinesia (Mirza et al. 2017).

Mechanisms
As the surgical process, the implanted pulse generator (IPG), the lead, and the extension are needed. The IPG is a neurostimulator which sends electrical pulses to the brain; the lead is placed in a nucleus of the brain. Lead implantation may take place under local anesthesia. A hole about 14 mm in diameter is drilled in the skull and the probe electrode is inserted stereotactically (Larson 2014). 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. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa. Because high-frequency stimulation had a therapeutic effect similar to that of ablative surgery, DBS was thought to function as a reversible lesion by inhibiting neurons near the stimulating electrode (Herrington et al. 2016). The cortical-basal ganglia-thalamo-cortical loop had been divided into a direct pathway which functioned to initiate and facilitate voluntary movement and an indirect pathwaythat inhibits movement. D1-receptor-expressing striatal medium spiny neurons (MSNs) project primarily to the direct pathway, and D2-receptor-expressing MSNs project primarily to the indirect pathway. Dopaminergic input from the substantia nigra pars compacta (SNc) to the striatum increases activity in the direct pathway via D1 receptors and decreases activity in the indirect pathway via D2 receptors, facilitating movement (Herrington et al 2016).

**Essential Tremor**
Essential tremor (ET) is the most common movement disorder, with a prevalence of 4.0–5.6% in persons over the age of 40 years; this rises to as high as 9.0% in people over the age of 60 years (Larson 2014). The tremor typically involves the upper extremities, but can also be present in the head, voice, and the lower extremities. Although the absence of resting tremor is often a differentiating feature between ET and PD, patients with ET can have a resting component to their tremor, as well as other features, such as tandem gait disturbance. The most commonly used target for DBS in ET is the Vim, and this is currently the only US FDA-approved target for DBS in the USA. Numerous studies report significant improvement with both unilateral and bilateral Vim stimulation, with long-term follow-up showing anywhere from 40% to 80% reduction in tremor severity and corresponding improvement in quality of life. Stimulation-induced adverse effects, including dysarthria, paresthesias, and ataxia can present in upwards of 30% of patients receiving bilateral stimulation. Although these are reversible by changing the stimulation parameters, this may complicate the clinician’s ability to program the device in a way that maximizes tremor control. Approximately 10% of patients do not have adequate tremor control with Vim stimulation (particularly those with a proximal component to their upper extremity tremor), and upwards of 15–20% of patients improve initially, but then lose efficacy within the first year of surgery Other targets have emerged as an alternative to the Vim for patients with ET. To date, the most widely studied area is inferior to the thalamus, and posterior and superior to the subthalamic nucleus (STN). Several targets have stimulated by different centers in this region, including zona incerta and the prelemniscal radiations, although as is the case with most DBS targets it is difficult to tell exactly where the mechanism of action is taking place. A broader anatomic term that incorporates both of these targets is the posterior subthalamic area (PSA). This region is of interest because it appears to provide tremor reduction that is comparable to Vim but may have a lower adverse effect profile, better efficacy with proximal and intention tremor, and may avoid the question of “tolerance” seen with Vim stimulation [41–45]. However, many of these early studies are small, others have a heterogeneous patient population that include disorders other than ET, and not all seem to have a rigorous analysis of stimulation-related adverse events. More recent studies have started to compare PSA to Vim directly, with better overall results seen with PSA stimulation. A number of centers have abandoned Vim DBS (particularly outside the USA), and our own center is starting to use the PSA in cases of failed Vim DBS. More work is needed in this area with prospective, randomized and blinded studies.

**Parkinson's disease**
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Parkinson's disease is a neurodegenerative disorder that affects predominately dopaminergic neurons in the substantia nigra. The symptoms include: tremor, slowness of movement (bradykinesia), limb rigidity, akinesia, and balance problems. The primary goals of the procedure for Parkinson's disease are elevating the level of dopamine in the brain (such as with carbidopa/levodopa, the most commonly used medication) and/or prolonging the action of the dopamine that is present. Most patients with PD typically start to develop complications of medical therapy after 5–15 years of treatment with these agents. These include motor fluctuations, dyskinesia and intolerance of increasing amounts of medications required owing to progression of disease and worsening PD symptoms. It is at this stage of PD when most experts advocate DBS for properly selected patients. Patient selection is perhaps the most important predictor of a good clinical outcome for DBS in PD, aside from proper electrode placement and appropriate stimulation parameters. One of the best predictors of response to DBS is an adequate clinical improvement with oral levodopa; most advocate at least a 25–30% improvement in the Unified PD Rating Scale Part III (clinician scored motor examination) between the off and the on medication state. Generally, symptoms that improve with oral levodopa will also respond to DBS; the one possible exception is tremor in patients with tremor dominant PD. Other factors that should be considered include confidence in the diagnosis, minimal presence of nonmotor symptoms (particularly cognitive decline and depression), minimal medical comorbidities, age, realistic expectations on the part of all parties involved, reasonable social support and the ability to handle the responsibilities of a complex therapy. Many centers perform on medication, off medication examinations, as well as full neuropsychological evaluations to assess many of these factors before deciding to proceed with surgery. The two targets used primarily for PD are the STN and the GPi. Both targets provide fairly equivalent improvements in the cardinal motor symptoms of PD, as well as dyskinesia. The most effective site of STN stimulation appears to be in the dorsolateral STN or just dorsal to the STN.

**Dystonia**
Dystonia is a movement disorder characterized by abnormal, sustained muscle contractions, often in agonist and antagonist muscle groups, which result in abnormal postures or repetitive movements. Dystonias occur in a variety of settings and, as such, are classified according to age of onset, anatomic distribution, and cause. Age of onset can be early (<26 years) or late; early-onset dystonia is a common movement disorder in the pediatric population. Anatomic distribution can be generalized (affecting the majority or all of the body), segmental (two adjacent body regions), multifocal (multiple regions that are not all adjacent), or focal (one body part, such as the hand in writer’s cramp). DBS is considered when medical treatments are either ineffective or not tolerated, and the degree of disability and/or disease burden on either the patient or caregiver is sufficiently high to warrant surgical intervention. Unlike the other movement disorders, dystonia is unique in that there are other “nonmotor” factors to consider prior to surgery. These include the caregiver and home environments (particularly for pediatric patients), how prominent pain is as a feature of the dystonia (and how that has been managed), and whether there is a fixed skeletal deformity present that would limit functional outcome. Historically, the target of choice for DBS in dystonia has been the GPi; although effective, there are some drawbacks to this target. These include stimulation-induced bradykinesia in previously asymptomatic body parts with bilateral implantation, and a delay of weeks, months, or even years between onset of stimulation and realization of maximal clinical benefit. This may reflect a different mechanism of action of DBS in dystonia, at least when using this target. More recently, the STN has been proposed as a target for primary and cervical dystonia. The STN may avoid stimulation-induced bradykinesia, but other issues, such as transient dyskinesia and possible weight gain in some patients, have been observed.

**Risk and Considerations**
Deep brain stimulation is generally a safe procedure and involves creating small holes in the skull to implant the electrodes, and surgery to implant the device that contains the batteries under the skin in the chest. Complications of surgery may include: bleeding in the brain, stroke, seizures, and infection. The most serious and worrisome risk occurs during the surgical procedure when “probes” called microelectrodes are inserted into the brain to determine the best target location. If a microelectrode, or alternatively the DBS lead, punctures a blood vessel it can lead to a stroke or stroke-like syndrome which may result in weakness, numbness, sensory loss, visual difficulties, or a host of other neurological problems.

**Glossary of terms**
Dystonia: a muscle contraction that causes repetitive movements and/or postures Essential tremor: a neurological disorder that causes involuntary and rhythmic shaking. Although it can affect several different parts of the body, the trembling occurs most often in the hands Parkinson’s disease: a motor system disorder that is correlated with a loss of dopamine in the brain and is characterized by tremors, muscular rigidity, and involuntary movements Subthalamic nucleus: part of the basal ganglia system that is involved in the indirect pathway

**Suggested readings**
- This article provides general information about benefits, risks, and options of DBS - It provides broader perspectives of DBS use in psychiatry and neurology.
 * Akbar U, Asaad WF.** A Comprehensive Approach to Deep Brain Stimulation for Movement Disorders. //Rhode Island Medical Journal// 100: 30-33, 2017.
 * Talan J**. Deep Brain Stimulation: A New Treatment Shows Promise in the Most Difficult Cases. New York, NY: Dana Press, 2009.
 * Williams NR, Okun MS.** Deep brain stimulation (DBS) at the interface of neurology and psychiatry. //The Journal of Clinical Investigation//. 123(11):4546-4556, 2013.

**Quiz questions**
1. (T/F) Currently, deep brain stimulation is a FDA-approved surgical procedure for Parkinson's disease, essential tremor, and depression. 2. (T/F) Subthalamic nucleus is targeted to treat Parkinson's disease 3. (T/F) The initial segment of globus pallidus is the best method to treat essential tremor. 4. Which is the following is not the possible side effect of DBS? A. Stroke B. Infection C. Seizure D. Joint pain 5. Which is the following is associated with Parkinson's disease the most? A. GABA B. Dopamine C. Substance P D. Glutamate 6. Briefly explain the surgical procedure of DBS. 7. Describe common symptoms of dystonia

Answer: 1. F 2. T 3. F 4. D 5. B

Reference
http://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Deep-Brain-Stimulation http://www.parkinson.org/understanding-parkinsons/treatment/surgery-treatment-options/Deep-Brain-Stimulation “Deep Brain Stimulation for Parkinson's Disease Information Page. National Institute of Neurological Disorders and Stroke, U.S. Department of Health and Human Services. http://www.ninds.nih.gov/Disorders/All-Disorders/Deep-Brain-Stimulation-Parkinsons-Disease-Information-Page.
 * Guridi J, Alegre M.** Oscillatory activity in the basal ganglia and deep brain stimulation. //Mov Disord//. 32: 64–69, 2017.
 * Herrington TM, Cheng JJ, Eskandar EN.** Mechanisms of deep brain stimulation. //Journal of Neurophysiology//. 115:19-38, 2016.
 * Larson PS**. Deep Brain Stimulation for Movement Disorders. //Neurotherapeutics// 11: 465-474, 2014.
 * Mandybur G, Gartner M**. (April 2016). Deep brain stimulation (DBS). Mayfield Brain & Spine Cincinnati. http://www.mayfieldclinic.com/PE-DBS.htm.
 * Mirza S, Yazdani U, Dewey Iii R, Patel N, Dewey RB Jr, Miocinovic S, Chitnis S**. Comparison of Globus Pallidus Interna and Subthalamic Nucleus in Deep Brain Stimulation for Parkinson Disease: An Institutional Experience and Review. //Parkinson's Disease.// 2017: 1–15. 2017.
 * Wicnmann T, DeLong MR**. Deep-Brain Stimulation for Basal Ganglia Disorders. //Basal Ganglia// 1: 65–77, 2011.