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. 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.
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. 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. 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 (adaptive DBS), that uses beta-band power of the subthalamic
local field potentials (LFPs) 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.
Short term comparisons An indirect systems analysis compared the DBS to the STN, DBS of the GPi, subthalamotomy, jejunal levodopa, and subcutaneous apomorphine, in the first 6 months. Different results were seen depending on dopamine responsivity and whether motor symptoms (UPDRS II) or activities of daily living (UPDRS III) were assessed: A short term
meta-analysis that primarily looked at changes within the first year found the STN to be better than the GPi for motor symptoms and activities of daily living, but they included studies that analyzed the targets separately. For activities of daily living (UPDRS II) with DBS during the dopamine unresponsive state, patients improved 50% with STN but only 20% with GPi. For motor symptoms (UPDRS III), there was a 50% with STN but only 30% with GPi-DBS. STN reduced dyskinesia by 64%, OFF time by 69%, improved QOL by 20%, Levodopa dose was reduced 50%. GPi insufficient data to assess for dyskinesia OFF time, and levodopa reduction. A meta analysis following 1148 patients for a year and with an equal distribution between groups found that both STN and GPi improved motor function, but in different ways. GPi preserved postural instability and gait disability better than STN. GPi did not produce any significant improvement over STN in motor symptoms during the on state, though a point estimate favored the use of GPi. Motor symptoms in the off state showed that STN did not produce any significant improvement over GPi, though again a point estimate favored the use of STN. STN had a larger dopamine reduction than GPi, while GPi improved depression more than STN after surgery. Compared to the GPi, the STN showed more improvement in off state motor symptoms and activities of daily living. Conversely, the GPi was better than the STN for on state motor symptoms and activities of daily living, similar to data from the Netherlands NSTAPS study.
Long term comparisons . A
Bayesian analysis comparing DBS with intestinal levodopa, subcutaneous apomorphine and best medical therapy found DBS and intestinal levodopa to be the superior treatments, though it did not distinguish specific nuclei as DBS targets. In the setting of this limitation, they found intestinal levodopa being the best at improving quality of life more and DBS being the best at reducing off time. A more specific Bayesian
Monte Carlo analysis comparing individual nuclei found bilateral STN, GPi and intrajejunal levodopa to be better than either subcutaneous apomorphine or best medical therapy. Amongst the three, STN had the greatest likelihood of improvement, though it was not statistically significant.
Conventional and closed-loop comparisons In a 2021 research study conducted by Alberto Priori, a comparative analysis was presented between the impacts on motor symptoms between conventional deep brain stimulation (cDBS) and closed-loop adaptive deep brain stimulation (aDBS) in patients with Parkinson's disease. This work highlighted the safety and effectiveness of aDBS stimulation compared to cDBS in a daily session, both in terms of motor performance and TEED to the patient. Simon Little has regarded aDBS approach to be superior to conventional DBS in PD in primates using cortical neuronal spike triggering and in humans employing local field potential biomarkers. While presenting a protocol for a pseudo-randomised clinical study for adaptive deep brain stimulation as advanced Parkinson's disease treatment, it was shown that aDBS do not induce dysarthria, in contrast to cDBS.
Post operative complications The overall rate of intracranial hemorrhage at surgery is 5%, with symptomatic hemorrhage in 2% and hemorrhage causing permanent deficit or death in 1%. Stroke occurred in 1%, infection in 8%, lead erosion without infection in 2%, lead fracture in 8%, lead migration in 10%, and death in 2%. Additional adverse events include the need for revision in 5%, lead malposition 3%, surgical site complications 3%, hardware-related complications 2%, and seizure 2%. There was a significant non-linear increase with each additional track, for example in situations when leads needed to be repositioned or in multiple target procedures. In the short term, studies have reported a risk of cerebral hemorrhage of 1.4%, hardware infection 1.1%, post operative mental status change occurred in 4.6%, and seizure occurred in 1.4%; in the longer term adverse events include confusion at 3.9%, hardware infection at 4.5%, implantable pulse generator malfunction 1.4%. Combined methods that use both microelectrode recording and image guidance are not as brief in operating room time and have a higher risk of hemorrhage, but result in more accurate lead placement.
Caregivers More than half of caregivers rate DBS to the STN negatively at one year after surgery. Some of the symptoms caregivers were unhappy about included mania, apathy, depression, impulsivity, compulsivity, aggressiveness and disinhibition. Children of individuals with Parkinson's tended to be happier than spouses. Concerns raised by caregivers included dyskinesia impacting the
physiognomy of their loved ones, leading to the inability to control movements and a glassy-eyed appearance. Family relationships changed between partners and children were also stressed because the empathy and self-awareness of patients diminished as they lost their sense of reality over time. The degree of dissatisfaction did not appear to correlate with the success of the surgery as far as motor symptoms, which generally improved. Similar dissatisfaction persisted at two years in a separate analysis, with almost 60% of caregivers continuing to report dissatisfaction. Despite the high dissatisfaction rate of caregivers with surgery, additional measures such as caregiver burden, psychiatric and cognitive functioning and caregiver quality of life remained relatively stable. In addition, both patients and caregivers reported that they would opt for DBS again.
Dyskinesia DBS for the GPi has a direct effect on dyskinesia reduction and is more effective than DBS to the STN, with the latter being dependent on dopamine reduction. As such, pallidal surgery is indicated when dyskinesia is a dose-limiting factor preventing higher levels of needed dopaminergic therapy. STN stimulation can also induce persistent contralateral dyskinesia, and in some cases require a repeat surgery to implant GPi rescue leads.
Gait The effect on gait is inconsistent, with multiple studies showing worsening of gait, balance and speech as potential complications of DBS, with DBS to the STN carrying a higher risk of gait dysfunction. A study delineating adverse effects by time found that though DBS mitigated gait symptoms after surgery, postoperative postural instability and gait disorders worsened in the long term. In the context of chronic levodopa therapy, the most relevant effect of STN neurostimulation is improvement of motor function during the off state, the period during which symptoms are non responsive to dopamine.
Genitourinary and other symptoms Benefit after STN DBS has been reported in nonmotor fluctuating symptoms, including urinary dysfunction,
sialorrhea, sleep, PD-related pain, and off-period sweating. Another meta analysis study further distinguished effects by target subgroups, finding that DBS of the GPi and STN have an inhibitory effect on
detrusor function at the
pelvic floor, leading to an increase in functional urine capacity and retention. DBS of the VIM has the opposite effect, leading to detrusor excitation and improved voiding.
Mortality Long term mortality rates with DBS measure up to 17% with an average age at death of 71 years, with the risk of mortality being more pronounced in cases of advanced disease. DBS of the STN has a three-fold increased mortality compared to the GPi in Parkinson's patients, with most deaths being due to postoperative complications and not directly related to the stimulation itself.
Neuropsychological effects and suicide Neurologic side effects of deep-brain stimulation include cognitive impairment, memory deficits, difficulties with speech,
disequilibrium,
dysphagia, and motor and sensory disturbances. Potential psychological side effects include mania, depression, apathy, laughter, crying, panic, fear, anxiety, and
suicidal ideation. It is important that individuals be screened before and after the procedure for suicidal ideation, impulsivity (e.g., gambling, impulsive shopping, hypersexuality, etc.), and dopamine dysregulation, an addiction-like syndrome associated with the use of levodopa. The STN, at approximately 160 mm3, is one-third the size of the GPi (on average 480 mm3) and has multiple nearby non-motor pathways, the inadvertent activation of which has been suggested to be the cause of
emotional dysregulation that can be seen when it is targeted. Cognitively, decreased verbal fluency and an increased risk for
dementia can occur due to the wire passing through the
prefrontal cortex and
caudate nucleus, a path more often seen with subthalamic stimulation than GPi due to its more inferomedial positioning. Long-term follow-up showed a more rapid decline in cognitive function with treatment targeting the subthalamic nucleus than that targeting the GPi. and a lifetime
incidence of 80%. One large meta-analysis suggested the likelihood of dementia increases by 2.5 fold, though the subpopulation in the analysis was limited in quantity. Another meta analysis suggested the incidence as the same. These effects can be due to misplacement of electrodes, miscalibration, or even well placed electrodes that inadvertently stimulate adjacent
limbic circuits adjacent to the target nuclei. Though
dopamine withdrawal syndrome due to the reduced dose of
levodopa required after surgery (typically 70%) could contribute to these findings, it does not completely account for them. Concerningly, though preoperative screening for depression and suicide are done to mitigate this risk, some studies have shown no evident difference in pre-operative depressive or cognitive status between suicidal and nonsuicidal individuals after surgery. The risk of suicide is more pronounced with treatment to the STN than the pallidus, with studies as soon as 6 months showing increased proxy symptoms of suicide such as depression, isolation, tearfulness, anger, anxiety and hallucinations. As with other neuropsychiatric effects that are more common with the STN, it is thought to be due to a combination of the levodopa dose reduction that occurs after surgery, adjacent subthalamic limbic circuit activation and disinhibition. and euphoria have been reported after DBS. Comparative studies between the STN and GPi have suggested higher depression rates for the STN. The improvement in motor symptoms but progressive deterioration of axial symptoms such as gait, vocal control, and neuropsychiatric side effects has led to a new phenotype of Parkinson's patient in the long term with mitigated or well controlled non axial motor symptoms, but with progressive worsening of axial motor symptoms (bradykinesia, dysarthria, postural instability, freezing of gait) and cognitive symptoms such as dementia and hallucinations. ) and cognitive decline, features which generally do not improve and can worsen after surgery. At baseline, the total lifetime risk of suicide in Parkinson's at baseline is 22% for ideation and 1% for attempts, with the general population at 13% ideation and 5% attempts.
Posture Parkinson's is often characterized by
camptocormia, a classic stooped
kyphotic posture that develops as the disease progresses as well as
Pisa syndrome, characterized by a persistent tilted posture. The impact of DBS to the STN or GPi on posture in Parkinson's have been heterogenous and inconsistent at best. Though some studies have shown positive effect, the quality of evidence is quite low. The
pedunculopontine nucleus (PPN) is being studied as a target for postural instability and
gait freezing, but clinical research is still in its early stages. It is located in the mesopontine tegmentum next to the crossing of the superior cerebellar peduncle and is theorized to play a role in reflex reactions, sleep-wake cycles, posture and gait.
Quality of life A study comparing quality of life and adverse affects from patient perspective found that DBS had a more positive effect on quality of life than subcutaneous apomorphine, intestinal dopamine and best medical therapy, but also the highest rate of adverse effects. A Bayesian analysis found intestinal dopamine has been shown to be superior to both DBS and best medical therapy for quality of life. Younger age, early onset of Parkinson's, less dyskinesia, and higher quality of life before surgery predict higher quality of life following the procedure.
Sleep The effects of DBS on sleep are heterogenous but it generally improves in quality over time. There is an increase of complex behavior during REM sleep after surgery independent of DBS target, while REM sleep without atonia increases with STN and decreases with GPi.
Speech and swallowing Almost 40% of patients develop speech impairment after DBS to the STN, with only 10% improving after reprogramming. DBS to the GPi improves speech, in contrast to the STN, thalamus or zona incerta. Up to 33% of patients can develop problems with speech after bilateral DBS to the STN, both by formal metrics and as subjectively reported by individuals and their families. This is less than that seen after thalamotomy (40%). The numbers are significantly lower for unilateral treatment, at 10-15%, but the symptomatic improvement with this is also one-sided, making it more appropriate for individuals with asymmetric disease. Swallowing function after DBS can be impacted, analysis showing that it is either stable or improved after DBS to the GPi and has more variable effect after DBS to the STN, possibly worsening in on medication states, but stable or improved in off states. Speech disorders are more common after STN surgery, though dysphagia is more common after DBS to the GPi, an important finding because
aspiration pneumonia is the most common cause of death in Parkinson's. The two nuclei have differing effects on the pedunculopontine nucleus, which in turn affects swallowing through the
solitary nucleus. The GPi inhibits the PPN, while the STN excites it. DBS of the VIM is more commonly done with tremor-dominant variants of Parkinson's and
essential tremor. It can cause dysarthria in about 20% of patients.
Methodological limitations In trials on interventions, symptom scales such as the
Unified Parkinson's Disease Rating Scale (UPDRS III) are typically used. These metrics measure motor function with a score from 0 to 108. Alternatively, the 39-item Parkinson's disease questionnaire (PDQ-39) has been utilized to measure disease specific quality of life with a score between 0 and 100. The effectiveness of an intervention is usually based on comparison of these scores in
treatment and control groups. It has been pointed out that a statistically significant numerical difference in a scale or questionnaire does not necessarily translate to a clinically meaningful impact for the individual. Beyond this, the scales can be subjective and susceptible to
placebo effects and physician bias.
Essential tremor Essential tremor, the most common movement disorder, is a chronic condition characterized by involuntary and rhythmic shaking. It was the first indication to be approved for DBS (alongside Parkinsonian tremor) and before DBS had a long history of being treated with ablative brain lesioning. Frequencies above 100 Hz are most effective for cessation of tremor, while lower frequencies have less effect. In clinical practice, frequencies between 80 and 180 Hz are typically applied. DBS electrodes commonly target the ventrointermediate nucleus of the thalamus (VIM) or ventrally adjacent areas in the
zona incerta or posterior thalamus. Multiple targets along the circuitry of the cerebellothalamic pathway (also referred to as the dentatorubrothalamic or dentatothalamic tract) have been shown to have similar therapeutic effect. Possible side effects of DBS for essential tremor include speech difficulties and paresthesia. Similar targets have previously been applied to treat essential tremor using surgical lesioning, for instance using
MR-guided Focused Ultrasound,
Gamma-Knife Radiosurgery or conventional
radiofrequency lesioning. The annual volume of
MRgFUS thalamotomies has overtaken DBS for treatment of tremor. aDBS may be an effective tool in the treatment of essential tremor (ET), which is one of the most common neurological movement disorders. aDBS for ET is however more focused on a closed-loop technology based on external sensors. In a recent study, H J Chizeck presented the first translation-ready training procedure for a fully embedded aDBS control system for MDs and one of the first examples of such a system in ET.
Dystonia DBS is also used to treat
dystonia, a
movement disorder characterized by sustained repetitive muscle contractions causing painful abnormal postures and involuntary movements. DBS is effective in treating primary generalized dystonia, and also used for focal variants such as cervical and task-specific dystonias. In studies targeting the GPi using high frequency DBS there were improvements of ~45% within the first six months of treatment. The applications of aDBS in the treatment of dystonia have significantly evolved over the past few years. Low-frequency oscillations (LFO) detected in the internal globus pallidus of dystonia patients have been identified as a physiomarker for adaptive Deep Brain Stimulation (aDBS). Moreover, the characteristics of pallidal low-frequency -namely, average low-frequency (LF) oscillatory power (4-12
Hz) - and beta bursts can be helpful in implementing adaptive brain stimulation in the context of parkinsonian and dystonic internal globus pallidus.[23] A significant amount of scientific research to date on pathological oscillations in dystonia has been focused to address potential biomarkers that might be used as a feedback signal for controlling aDBS in patients with dystonia.
Obsessive–compulsive disorder DBS for OCD, Tourette's Syndrome, and dystonia were first completed in 1999. The original target studied was the
anterior limb of the internal capsule, one thought to corresponding to the
direct pathway in the basal ganglia to the subthalamic nucleus and other midbrain regions, the other
indirect. A potential circuit structure that seems to combine most effective targets in both the ALIC and STN region has been identified and termed the OCD response tract, though multiple targets have been probed and found to have effect. DBS for OCD received a
humanitarian device exemption from the FDA in 2009. In Europe, the CE Mark for Deep Brain Stimulation (DBS) for obsessive–compulsive disorder (OCD) was active from 2009 to 2022 but not renewed due to a lack of government health coverage.
Epilepsy DBS has been studied for treatment resistant epilepsy with seizure foci not amenable to surgical resection or
vagus nerve stimulation; almost 40% of individuals with the disease are inadequately treated with medication alone.
Responsive neurostimulation is a form of adaptive brain stimulation that targets the
anterior nucleus of the thalamus. The anterior nuclei of the thalamus is the only FDA approved target for epilepsy treatment, with some individuals achieving more than a 50% decrease in seizures. Other brain regions being studied as potential targets include: • Centromedian nucleus (CM): Located in the thalamus, CM-DBS has been used in some cases of generalized epilepsy, including
Lennox-Gastaut syndrome. It targets the thalamocortical networks involved in seizure propagation and has been reported to help reduce seizure severity and frequency. • Hippocampus: Particularly in patients with temporal lobe epilepsy, hippocampal DBS has been investigated as an option due to its role in seizure propagation and memory function. Studies have generally shown promising results, particularly for temporal lobe seizures.
Tourette syndrome DBS has been used experimentally for individuals with severe
Tourette syndrome that do not respond to conventional treatment. Despite early successes, DBS remains a highly
experimental procedure for the illness, with more study needed to fully understand its clinical effects. 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". The first clinical use of DBS for Tourette's Syndrome was carried out in 1999 The procedure is invasive and expensive and requires long-term expert care and its benefits for severe Tourette's are inconclusive. Tourette's is more common in children, tending to remit spontaneously in adulthood, limiting the applicability of surgery in these populations. It also may not always be obvious how to utilize DBS for a particular person because the diagnosis of Tourette's is based on a history of symptoms rather than an examination of neurological activity. The
Tourette Association of America recommends that the procedure be reserved for adults with severe debilitating treatment resistant variants of the disease, and without comorbidities such as substance abuse or personality disorders.
Depression Though depression can be a contraindication for electrostimulation of other chronic neurologic diseases in the basal ganglia, the therapy can also be used for treatment of severe depression. The target for electrostimulation in depression is more
anterior and superficial at the frontal lobes, as opposed to other motor disorders where it is deeper in the basal ganglia. Beginning in the 1950s, treatment has been attempted in the
subcallosal cingulate region and the ventral capsule/ventral striatum have shown mixed outcomes.
Diffusion-weighted imaging based tractography has led to the theoretical discovery of the so-called 'depression switch', the intersection of four bundles that allowed more deliberate targeting of DBS in the subcallosal area and improved results in additional open-label studies. While anatomical descriptions as well as supposed mechanisms for this target site have been debated, clinical effects of this DBS target in patients with TRD have been promising.
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 people, but results vary. One study of 17 people with intractable cancer pain found that 13 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. DBS has also been applied for
phantom limb pain. == Adverse effects ==