Deep brain stimulation
Deep brain stimulation is a type of neurostimulation therapy in which an implantable pulse generator is surgically implanted below the skin of the chest and connected by leads to the brain to deliver controlled electrical impulses. These charges therapeutically disrupt and promote dysfunctional nervous system circuits bidirectionally in both ante- and retrograde directions. Though first developed for Parkinsonian tremor, the technology has since been adapted to a wide variety of chronic neurologic disorders.
The exact mechanisms of DBS are complex and not fully understood, though it is thought to mimic the effects of lesioning by disrupting pathologically elevated and oversynchronized informational flow in misfiring brain networks. As opposed to permanent ablation, the effect can be reversed by turning off the DBS device. Common targets include the globus pallidus, ventral nuclear group of the thalamus, internal capsule, and subthalamic nucleus. It is one of the few neurosurgical procedures that allows blinded experiments, although most studies to date have not taken advantage of this discriminant.
Since its introduction in the late 1980s, DBS has become a major research hotspot for surgical treatment of tremor in Parkinson's disease, and the preferred surgical treatment for Parkinson's disease, essential tremor, and dystonia. Its indications have since extended to include obsessive–compulsive disorder, refractory epilepsy, chronic pain, Tourette syndrome, and cluster headache. In the past three decades, more than 244,000 patients worldwide have been implanted with DBS.
DBS has been approved by the Food and Drug Administration as a treatment for essential and Parkinsonian tremor since 1997 and for Parkinson's disease since 2002. It was approved as a humanitarian device exemption for dystonia in 2003, obsessive–compulsive disorder in 2009, and epilepsy in 2018. DBS has been studied in clinical trials as a potential treatment for chronic pain, affective disorders, depression, Alzheimer's disease, and drug addiction, amongst others.
Device components
The DBS system consists of three components: a neurostimulator known as an implanted pulse generator, its leads, and an extension. The neurostimulator comprises a titanium housing and a battery that sends electrical pulses to the brain to interfere with neural activity through deafferentation.The leads are two coiled wires insulated in polyurethane with four platinum-iridium electrodes that allow delivery of electric charge from the battery pack implanted in the chest wall. The battery is usually situated subcutaneously below the clavicle and rarely in the abdomen. The leads, in turn, are connected to the battery by an insulated extension wire which travels from the chest wall superiorly along the back of the neck below the skin, behind the ear, and finally enters the skull through a surgically made burr hole to terminate in the deep nuclei of the brain. Microelectrodes are delivered through the burr holes. A combination of microelectrode recordings, microstimulation, macrostimulation, and neurophysiological mapping at the level of single neurons or local neuronal populations through local field potential analyses are used to increase the specificity of placement for the most precise neurophysiologic effect possible.
After surgery, battery dosage is titrated to individual symptoms, a process that requires repeat visits to a clinician for readjustment.
DBS leads are placed in the brain according to the specific symptoms to be addressed, and implantation may take place under local or general anesthesia. A hole about 14 mm in diameter is drilled in the skull, and the probe electrode is inserted stereotactically, using either frame-based or frameless stereotaxis. During the awake procedure with local anesthesia, feedback from the individual is used to determine the optimal placement of the permanent electrode. During the asleep procedure, intraoperative MRI is used to image the brain during device placement. The installation of the IPG and extension leads occurs under general anesthesia.
Clinical usage
The surgery is utilized in Parkinson's to help with motor symptoms and reduce dopaminergic medication, but it does not usually help with axial non motor symptoms such as posture, gait instability, mechanical falls, and can have adverse effects such as loss of cognitive function, depression, apathy, and suicide.The selection of the correct individual to have the procedure is a complicated process. Multiple clinical characteristics are taken into account, including identifying the most troubling symptoms, current medications, and comorbidities. Surgery and aftercare are typically managed by multidisciplinary teams at specialized institutions. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.
The surgery is usually contraindicated in individuals who have dementia, suffer from depression or other psychiatric disorders, or who have frequent falls despite being in their best on-drug state. Systematic assessment of benign or even beneficial precursor symptoms of a hyperdopaminergic syndrome, such as do-it-yourself activities, creativity, and nocturnal hyperactivity, also helps prevent the devastating behavioral addictions or impulse-control disorders that can occur after the procedure.
Stereotactic MRI is used to localize the target nuclei, though it is more susceptible to anatomic field distortion than ventriculography; the latter is not done anymore as it is considered too invasive for its benefit with anatomic precision and the advent of high Tesla intraoperative MRIs. The awake variant of the surgery allows symptom testing in real time. Several motor symptoms, except gait, can be evaluated; however, wrist rigidity is often done because it does not require the patient's active participation and can be scored in the operating room by use of a semi-quantitative scale. Speech and tremor can also be assessed in real time, though speech may be difficult to evaluate due to fatigue that occurs for the patient during the later hours of the procedure. When the best tract has been identified, the corresponding microelectrode is removed and replaced by a permanent lead. Because of its larger size, the GPi does not necessarily require microrecording prior to placement of a chronic lead, leading to a reduced risk of hemorrhage or cognitive deficit.
Postoperative programming after DBS is complex and personalized, but poorly standardized across institutions despite decades of research. In practice, it is still an iterative trial-and-error-based process. Parameters are initially set based on experience and then adjusted according to individual clinical response. Though this works for symptoms that respond quickly to stimulation, such as tremor, for other symptoms with a more delayed or nuanced response profile, it carries the risk of chronic overstimulation leading to adverse events, including impairment of gait and speech. Inappropriate stimulation can also cause non-motor side effects such as impaired cognition or manic disinhibition. Such effects are usually energy-dependent and reversible with adjustment. Though it is recognized that the most important parameter in stimulation is frequency over voltage or pulse-width, there is no global consensus about the initial parameters of DBS, nor is there a protocol for stimulation options in case of poor outcome.
In distinction to DBS, although surgical lesions in the globus pallidus improve dyskinesias and Parkinsonian symptoms, they are irreversible and carry a risk of permanent neurologic deficit. Similarly, lesions of the STN improve Parkinsonian symptoms, but can cause hemiballism.
Parkinson's disease
DBS is used to manage Parkinson's disease symptoms that are resistant to medication. The ideal candidate for DBS is one who does not have dementia, is not severely depressed, and who does not have falls while being in their best on-drug state, but who does have disabling motor fluctuations or dyskinesias that necessitate bilateral surgery. It is treated by applying high-frequency stimulation to target structures in the deep subcortical white matter of the basal ganglia. Frequently used targets include the subthalamic nucleus, globus pallidus internus, and ventrointermediate nucleus of the thalamus. Neurostimulation can be considered for people who have Parkinson's with motor fluctuations and tremors inadequately controlled by medication, or to those who are intolerant to medication as long as they do not have severe neuropsychiatric problems. A >30% degree of symptom responsiveness to dopamine is a strong predictor of a good response to DBS surgery, though it is not mandatory. This has led most centers to require evaluation both on and off dopamine prior to the procedure to increase the likelihood of success. DBS is not currently considered to be a disease-modifying treatment. Shorter disease duration pre-operatively tends to lead to better results after surgery. The response from DBS is only as good as the patient's best "on" time, with the exception of tremor, which may show greater improvement than that seen with medication.Target and therapy comparisons
Initially, the STN was considered superior to the GPi for tremor reduction, rigidity, and bradykinesia as well as enabling greater reductions in dopaminergic medication following surgery and the GPi superior for reducing dyskinesia. Longer-term studies have found the two targets to be equivalent in motor symptoms, but both relatively ineffective for cognitive and axial motor symptoms of Parkinson's disease such as gait, posture and speech.Comparison of the STN and GPi in DBS is also inconsistent due to different medical centers tending to have better results with specific nuclei and studies focusing on short as opposed to long term results. The three most commonly studied targets to date are the globus pallidus internus, subthalamic nucleus and ventrointermediate nucleus. DBS has also been compared to infusion therapies such as intestinal levodopa and subcutaneous apomorphine. The vast majority of DBS research to date has been on the subthalamic nucleus.
A large inclusive meta analysis that compared the STN to the GPi between 6–12 months found the STN to be superior for motor symptoms and activities of daily living, but found studies to be too heterogenous or insufficient to compare the targets for dyskinesia, daily off time, quality of life, or levodopa reduction.
In longer-term studies, however, the impact of the two nuclei on motor symptoms equalizes, but the GPi becomes superior to the STN for improvement of activities of daily living and dyskinesia. Conversely, the STN is superior to the GPi for reduction of dopamine medication. Both short and long term analyses showed the targets to be equivalent as far as adverse events.
A meta-regression showed that combined with levodopa, the GPi preserved postural instability and gait disability better than the STN. Gait or dysarthria are often unaffected or even worsened by DBS, particularly in ON medication state. When comparing 60 vs 130 Hz, 60 Hz frequency substantially reduced gait freezing, but subsequent studies have not replicated this, often finding worsening motor symptoms and less gait benefit with lower frequencies. A recent retrospective study showed 64% of patients had subjective improvement of axial symptoms when switching from higher to lower frequency stimulation with increased voltage.
Since 2015, several experiments were carried out to assess the efficacy of aDBS, that uses beta-band power of the subthalamic local field potentials as target to adapt DBS parameters to motor fluctuations. Results of the experiments proved that aDBS is highly effective in controlling the patients PD symptoms in addition to the normal Levodopa therapy, reducing dyskinesias.