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|Year : 2015 | Volume
| Issue : 1 | Page : 9-18
Deep brain stimulation: Current status
Sanjay Pandey, Neelav Sarma
Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India
|Date of Web Publication||4-Mar-2015|
Dr. Sanjay Pandey
Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
In the last two decades, applications of deep brain stimulation (DBS) have expanded rapidly in the field of neurosciences. The most common indications for DBS are Parkinson's disease, medically refractory seizures, essential tremors, and primary dystonia. This device has also been used as an investigational tool in patients having Tourette's syndrome, tardive dyskinesia, and refractory seizures. In the field of psychiatry, DBS has been used for the treatment of refractory obsessive compulsive disorder and depression. The complications are mainly related to surgery, the device, and its stimulation. This article provides an overview of the current status and recent advances in the field of DBS.
Keywords: Parkinson′s disease; dystonia; tremor; device; surgery
|How to cite this article:|
Pandey S, Sarma N. Deep brain stimulation: Current status. Neurol India 2015;63:9-18
| » Introduction|| |
Deep brain stimulation (DBS) is a safe and effective treatment modality for certain neurological and psychiatric disorders. In the 1960s, ablative stereotactic surgery was employed for a variety of movement disorders including Parkinson's disease (PD), but was largely abandoned in the 1970s because of introduction of highly effective drugs like levodopa. In due course, however, it became obvious that levodopa and other anti-Parkinsonian drugs produced complications such as motor fluctuations, dyskinesias, hallucination, and psychosis, thereby limiting their utility. This led to a resurgence of surgical modalities as treatment options. Surgeons initially utilized ablative procedures; more recently, DBS has largely replaced the ablative methods as the procedure of choice as it is much less invasive. It is also reversible and adjustable.
The turning point for the utilisation of DBS in the management of movement disorders was the publication by Benabid et al. in 1987 on the efficacious stimulation of ventral intermediate nucleus of the thalamus for treatment of PD.  Subsequently, Bergman et al. in 1990 and Aziz et al. in 1992 demonstrated the efficacy of selective bilateral subthalamic nuclear (STN) lesioning in the treatment of primates in whom Parkinsonism More Details had been artificially developed with the help of the neurotoxin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). ,
Since its approval by the Food and Drug Administration (FDA) for PD in 2002, DBS has become a viable therapeutic modality for patients suffering from neurological and psychiatric disorders.
| » Technique|| |
In the DBS procedure, the stimulation electrodes are implanted into specific regions of the brain. An implanted, externally programmable pulse generator delivers continuous high-frequency electrical stimulation akin to a cardiac pacemaker.  The aim of DBS is to alter the physiology of a group of neurons within the basal ganglia or the thalamus. The localization is done by radiological and physiological landmarks. The radiological localization is performed by identifying the anterior commissure (AC), posterior commissure (PC), and the border between the internal capsule (IC) and the thalamus by using both computed tomography (CT) and magnetic resonance imaging (MRI) scans through a CT/MRI fusion technique. Stereotactic ventriculography provides a better localization, but is not the currently preferred technique because it is invasive and may not always be successful due to the difficulty encountered in cannulating an undilated ventricle.  Physiological localization helps in identifying different basal ganglia and thalamic nuclei on the basis of their electrophysiological properties. These properties include spontaneous activity, neuronal response to passive and active movements, and sensory responses to natural or electrical stimulation. Microelectrodes are used to isolate single action potentials. ,, These microelectrodes have a high impedance, facilitating isolation of single frequencies.  The STN is localized by its typical firing patterns (bursting pattern characterized by asymmetrical spikes at high frequency which shows proprioceptive response to passive movements). Since substantia nigra pars reticularis is immediately below the STN, it is important to recognize the neuronal activity of substantia nigra also (symmetrical spikes having a large amplitude with no response to external stimuli).  The electrode implantation is preferably performed under local anesthesia. Occasionally, this may also be done under general anesthesia, but the beneficial effects of DBS on the patient's symptoms will not be apparent during surgery. After establishing multiple tracks using physiological localization, the neurophysician directly assesses the effects of DBS at various locations. This is the most important step in deciding the site of microelectrode placement and is pivotal for the success of the DBS procedure. Testing for rigidity of movements at the wrist is the easiest way to assess the beneficial effects of surgery as it does not require the active participation of the patient. Tremor may also be assessed during surgery; however, intraoperative assesment of speech and bradykinesia is difficult. Once the best track with maximal beneficial and minimal side effects has been established, the microelectrode is replaced by a lead that is fixed to the skull. Following the successful intracranial lead placement, a pulse generator is placed at the subclavian region in a subcutaneous pouch under general anesthesia. However, some groups prefer to perform this step a week after the insertion of the electrode. A postoperative MRI helps in ensuring proper placement of the electrodes within the brain. The next important step is the programming of the device in which the neurophysician adjusts the voltage, frequency, and polarity settings to achieve the best possible outcome [See [Table 1]].
|Table 1: Post procedural programming of the deep brain stimulation (DBS) hardware |
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| » Mechanism of Action|| |
The exact mechanism by which DBS exerts its action is still not clear. It has been proposed that its effects depends on stimulation rather than creation of a lesion. Mechanisms by which it produces a functional inhibition include 1) neuronal message jamming (that is transmitted through the stimulated structure) and desynchronization of abnormal oscillations; ,, (2) inhibition of neuronal firing; , (3) combined induction and excitation of high-frequency bursts; and, (4) inhibition of neurotransmitter release. 
DBS in PD
The preferred targets for DBS in PD patients are the bilateral subthalamic nuclei. The response to DBS is quantified by a unified PD rating scale (UPDRS). It is divided into part I, II, III, and IV that assess non-motor experiences, motor experiences, motor examination, and drug-induced dyskinesias (including motor fluctuations), respectively. Patients with PD who have cardinal symptoms of the disease are likely to improve significantly. ,, Patients showing significant improvement with the optimum adjustment of anti-PD drugs are likely to show a similar improvement after proper placement of the electrodes within the STN. , Studies have shown unequivocal improvement in patients in part II and III UPDRS. ,,, DBS alleviates the same symptoms of PD that are relieved by levodopa. In addition, DBS also helps in reducing dyskinesias and non-dopa-responsive tremors. The contraindications to its usage include the presence of dementia and cognitive deficits. These features may get exacerbated after a DBS procedure. Stimulation of either the STN or the globus pallidus internus (Gpi) has shown statistically significant improvement in the UPDRS scores.  Comparison between the effects of the two stimulation sites have not shown any superiority of one over the other.  In a study, 159 patients were randomly assigned to Gpi (n = 89) and STN (N = 70) DBS. At a follow-up after 36 months, the motor symptoms were stable and did not differ in the two groups.  However, one study has found that STN stimulation achieves a greater improvement in the UPDRS and the other disability scores and also ensures a more sustained benefit through medicines for PD.  A high baseline score on section III (motor) of the UPDRS and good baseline levodopa responsiveness are independent predictors of a greater improvement in the motor score after surgery.  The other candidates in whom DBS shows a sustained benefit include those with motor fluctuations and dyskinesias who do not respond well to medical therapy. , In a recent study, neurostimulation was studied in patients with PD with early motor fluctuation. STN stimulation was found to be superior to the medical therapy in them.
Several studies and a meta-analysis have indicated that there was a significant improvement in the UPDRS part II and part III scores and also reduction in the medication administered in the "off period" following the DBS when compared to the pre-surgery medication being administered for the same state. ,, The reduction (43-57%) in part III UPDRS was also found to be sustained in studies where patients were followed up for 2-4 years .,,,,,, Tremor and rigidity were found to have an improvement of 70-75%, while akinesia improved by 50% in a study.  The mean reduction in the postoperative levodopa requirement was in the range of 50-56%. , There was a reduction of levodopa-induced dyskinesias and in their duration by 69% and 71%, respectively. , One of the symptoms that improves less when compared to the other ones is speech.  As a result of involvement of the cortico-bulbar fibres the patients may have increased dysarthria.  In terms of quality of life, a multicentric trial compared the impact of DBS along with optimal medical therapy versus optimal medical therapy alone and found greater improvement in mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort in the former group when compared to the medical therapy alone.  Factors that predict response to DBS include the age of the patient and his/her response to levodopa therapy. , An age of less than 65 years predicts an improvement in the quality of life; good results, however, have also been reported in patients in a more advanced age.  Factors such as freezing of gait that do not respond to levodopa also respond poorly to DBS therapy [Table 2] and [Table 3]. 
|Table 2: Recent studies of deep brain stimulation in Parkinson's disease|
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DBS in dystonia
Before DBS, apart from botulinum toxin, there were hardly any options available for patients with dystonia (especially generalized dystonias). The preferred site for DBS in dystonic patients is the GPi in the basal ganglia; however, STN stimulation has also been successfully used. ,,, DBS produces a good response in patients having a primary dystonia, especially generalized dystonia. The other types of dystonia where it is also effective include the cervical dystonias and tardive dystonia. ,, Results are better in young patients with a shorter disease duration.  Moreover, unlike other diseases, the beneficial effect of DBS in dystonia is delayed by weeks or months after the procedure.  The target localization of GPi for DBS in dystonic patients is difficult to achieve as compared to the STN localization in patients with PD. This is because younger patients manifesting a dystonia have difficulty in cooperating during the awake surgery; no definite thumbprint of the neurophysiological target is available; and, no intraoperative changes occur on stimulating the target site. Nevertheless, studies have demonstrated a 50% reduction in the disability of patients suffering from primary generalized dystonia.  Similarly, patients having a cervical or tardive dystonia improve by 40-90%.  The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) for evaluating generalized dystonia, and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for assessing cervical dystonia, are useful tools to grade the severity of the disease and the response to treatment. ,,, DBS has also been found to have long-term beneficial effects. ,,, Results in secondary dystonia have also been encouraging. In a study of 13 consecutive patients (that included 9 patients having a secondary dystonia), 11 had global subjective gains and notable objective improvement, but the benefits were variable and not completely predictable.  In another study, bilateral Gpi DBS was performed in adults with dystonic-choreoathetotic cerebral palsy. There was a significant improvement in pain, functional disability, and mental health-related quality of life.  In a multicentric (16 centers) study, 23 patients having neurodegeneration due to iron accumulation in the brain were treated with bilateral GPi DBS. At a follow up of 9-15 months, 66.7% of patients had 20% or more improvement in the severity of dystonia and 31.3% had 20% or more improvement from their pretreatment disability status.  In another multicentric study of 15 patients of choreoacanthocytosis who underwent DBS of the GPi, the short- and long-term outcomes were analyzed. These patients had a significant improvement in their unified Huntington's disease motor and functional capacity scores [Table 4] and [Table 5]. 
|Table 5: Deep brain stimulation in dystonia: Recommendations (EFNS)2011 |
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DBS in tremor
Besides the resting tremors in PD, other tremor types amenable to DBS include the essential tremors (ET), cerebellar tremors, and Holmes' tremors. In spite of the multiple pharmacological options available for ET, the symptoms in the vast majority of the patients are not well controlled. The targets for DBS in this condition are the ventral intermediate (Vim) nucleus of the thalamus and the STN. Vim-DBS has been found to be effective in ET. , It has a beneficial effect on appendicular, head, and vocal tremors.  Studies have shown unequivocal improvement in tremors that are otherwise refractory to medical therapy. ,, In a study, Vim-DBS reduced the amplitude, frequency, regularity, and tremor-EMG coherence of ET in comparison to controls.  Pharmacological treatment fails to change the characteristics of tremor other than in reducing its amplitude. Studies have also shown a better response in bilateral thalamic stimulation as compared to unilateral thalamic stimulation.  The tremor control has been found to be sustained for up to 6 years following the implantation.  In a study, 25 out of 39 patients (20 PD, 19 ET) with electrode implantations in the Vim were evaluated at 2 and 6-7 years.  Kinetic and postural tremors improved (P < 0.025) at follow up in patients suffering from ETs and there was also a significant improvement in functions of their hands (P < 0.025). Other types of tremors such as Holmes tremor have also been found to respond well to DBS.  Recent studies have shown a trend toward better response to zona incerta stimulation when compared to STN stimulation [Table 6] and [Table 7]. ,
|Table 6: Important studies of deep brain stimulation in essential tremor|
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|Table 7: Deep brain stimulation in essential tremor: Recommendations (American Academy of Neurology 2011) |
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| » DBS in Psychiatric Disorders|| |
DBS has also been found to be useful in certain psychiatric conditions such as obsessive compulsive disorders (OCD), Tourette's syndrome, and depression. The target for DBS in OCD is the anterior limb of IC.  DBS provides a sustained relief over a long period of time.  DBS has been found to be a viable option in patients suffering from Tourette's syndrome who have persistent symptoms in spite of optimized medical therapy. The plausible targets for DBS in this condition include the midline intralaminar nuclei of the thalamus, the motor and limbic portions of GPi, and the anterior limb of the IC. , Significant improvement in motor and vocal tics has been found following the DBS with the reduction of sensory urge that accompanies such patients. The DBS target for depression, unlike the psychiatric conditions mentioned above, is not well defined. A study of six patients with refractory depression found some clinical benefit in stimulating the subgenual cingulate region. 
| » Complications of DBS|| |
The occurrence of intracerebral hemorrhage has been found in up to 4.5% patients in various studies. ,,, Symptomatic hemorrhage has been found to be present in 2% of the cases, while 1.3% have an asymptomatic hemorrhage.  The important risk factors for hemorrhage in this setting include hypertension and an elderly age. The technical risk factors include a misplaced sulcal or ventricular trajectory [Table 8]. 
|Table 8: Important studies of deep brain stimulation related complications|
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A meta-analysis of 35 open label trials found the incidence of infection in 4.7% of the patients following the DBS procedure. , No significant difference in the infection rate was found in patients receiving the STN stimulation versus those receiving the GPi stimulation.  The highest risk of infection was in the first month following surgery.  The intracranial components of DBS are less likely to get infected when compared to the connector and the subcutaneous pocket lodging the implanted programmable generator.  Studies have reported a reduction in infection rates by local application of neomycin-polymyxin. 
The rate of death ranges from 0 to 4.4%. , This variability may be explained by the different inclusion criteria used in assessing perioperative complications such as myocardial infarction, pulmonary embolism, and pneumonia. ,,
Other surgery- and hardware-related complications
Rare complications of surgery include cerebrospinal fluid leak, pneumonia, and pulmonary embolism. Hardware-related complications are rare and include lead fracture and migration, erosion, and malfunction of the device.
Electrical stimulus related complications
A meta-analysis of 1398 patients found the incidence of depression to be approximately 8% in patients after the DBS procedure. , It could not be established whether this symptom was due to the procedure of DBS or it was a part of the progressive neuronal loss that occurs in conditions like PD. , A comparative analysis between the STN and GPi DBS found an increased incidence of depression in the former group 24 months following the procedure. The incidence of suicides has been found to be higher in patients who receive STN DBS when compared to the general population and patients treated for PD. 
Language and speech
DBS, especially of the STN, has been associated with decreased verbal fluency. It is, however, unclear whether this complication is due to the procedure itself or occurs as a result of decreasing the dopaminergic medications following the DBS procedure. ,
A study on the effects of DBS on STN found speech intelligibility to be reduced by an average of 14.2% ± 20.15% without medication, and by 16.9% ± 21.8% when continued on medication 1 year after the DBS. A decrease of 3.6% ± 5.5% and 4.5% ± 8.8%, respectively, was observed in the non-surgical control group during the same period.  Medially located electrodes were associated with a higher risk of speech deterioration.
DBS especially of the STN has been found to be associated with an increased incidence of postural instability and gait dysfunction.  Similar to language dysfunction, it is unclear whether these deficits appear as a result of the stimulation itself or as a result of decrease in the usage of dopaminergic medications. Patients who undergo DBS of the GPi, however, appear relatively resistant to these abnormalities. ,
| » Conclusion|| |
DBS is evolving as an effective treatment modality in certain neurological and psychiatric conditions. It has become an indispensible option for patients who are otherwise refractory or have a poor response to medical therapy. With proper preoperative selection and follow-up, it can be the key to a better lifestyle for patients whose disability may not improve with medications [Table 9] and [Table 10].
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]
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