Deep brain stimulation reduce tremors and muscle rigidity that are the hallmark of Parkinson’s disease


In a new study of seven people with Parkinson’s disease, Johns Hopkins Medicine researchers report evidence that deep brain stimulation using electrical impulses jumpstarts the nerve cells that produce the chemical messenger dopamine to reduce tremors and muscle rigidity that are the hallmark of Parkinson’s disease, and increases feelings of well-being.

“While deep brain stimulation has been used for treating Parkinson’s disease for more than three decades, the mechanism of action is not fully understood,” says Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and a member of the research team.

“Our study is the first to show in human subjects with Parkinson’s disease that deep brain stimulation may increase dopamine levels in the brain, which could be part of the reason why these people experience an improvement in their symptoms.”

Their findings are reported in the April issue of Parkinsonism and Related Disorders.

Parkinson’s disease is a neurodegenerative disease that affects an estimated 10 million people worldwide and strikes about 50,000 Americans each year, most of them over 50 years of age, according to the National Institutes of Health.

The disease is caused by the progressive death of nerve cells that produce the neurotransmitter dopamine.

Symptoms generally worsen over time, affecting both movement and mental health.

Deep brain stimulation is usually the next line of treatment when dopamine-enhancing medications, such as levodopa, fail to relieve Parkinson’s symptoms.

In a procedure similar to inserting a heart pacemaker, surgeons implant wires connected to an electrical current source, and in a controlled fashion, send tiny jolts of electricity through brain tissue to change how nerve cells fire.

Typically, to treat Parkinson’s disease, electrical current is passed in brain areas that receive chemical messages from dopamine-producing cells, rather than the dopamine-producing cells themselves.

Much of what is known about how electrical stimulation changes brain activity in patients with Parkinson’s disease has come from positron emission tomography, or PET imaging.

PET scans detect signals coming from radioactive tracers that are bound to specific molecules in the body.

Previous PET imaging studies using a tracer for glucose show an increase in brain metabolism after electrical stimulation, indicating a return to a more normal brain activity after the treatment.

However, PET studies using a tracer that binds to target sites, or receptors, on dopamine-receiving cells showed no change in dopamine levels after electrical stimulation, suggesting that dopamine may not play a role in improving brain activity and, by extension, easing Parkinson’s disease symptoms.

However, scientists suspect that dopamine might still play a key role in the success of deep brain stimulation.

“We knew that dopamine-producing cells get connections from many parts of the brain,” says Kelly Mills, M.D., M.H.S., assistant professor of neurology at the Johns Hopkins University School of Medicine.

“So, even if dopamine-producing cells are not activated directly, electrically stimulating other parts of the brain, particularly those that receive information from dopamine-producing cells, can indirectly increase dopamine production, but supporting evidence in patients was generally lacking.”

To study the change in dopamine levels after deep brain stimulation more precisely, the researchers went in search of other ways to track this chemical messenger in the brain.

Of the many molecules that dopamine interacts with, a protein called vesicular monoamine transporter, VMAT2, caught the researchers’ attention.

VMAT2 catches free-floating dopamine molecules and packs them into biological cargo bags called vesicles heading towards nerve terminals to release their content.

PET scans of VMAT2 on Parkinson’s disease patients taking dopamine-increasing medications, such as levodopa, show that brain dopamine and VMAT2 are related to each other: As dopamine levels in the brain go up with levodopa, VMAT2 levels go down, and vice versa.

To investigate if deep brain stimulation increases dopamine, the researchers performed PET scans of patients with Parkinson’s disease using a tracer for VMAT2.

They also performed PET scans using a tracer for glucose to measure changes in brain activity after the intervention.

The study included three white women and four white men, ages 60–74. These patients received PET scans before deep brain stimulation and then after.

In addition, the researchers evaluated the patients’ motor symptoms using the Movement Disorder Society Rating Scale and psychological symptoms using a battery of tests including the Hamilton Depression Rating Scale and Neuropsychiatric Inventory before and after electrical stimulation.

Trained psychometricians assessed the cognitive abilities of the patients before and after deep brain stimulation.

As expected, the researchers found that after deep brain stimulation, Parkinson’s patients had considerably fewer tremors and less rigidity. In addition, the patients also showed improvement in cognitive abilities and mood, with depression scores lowering by as much as 40 percent.

Analyzing PET scans, researchers saw that after deep brain stimulation, all seven patients had lower levels of VMAT2, implying that there was an increase in dopamine levels in the brain.

The PET scans for glucose showed that after electrical stimulation, brain activity in these patients had improved in areas that coordinate movement, mood and cognition. Furthermore, the PET scans for VMAT2 and glucose corresponded with each other, suggesting that the increase in dopamine may be one of the key mechanisms by which brain activity returns to normal after electrical stimulation, says Mills.

“We were able to see an increase in dopamine levels because we changed the way we looked at the problem,” says Mills.

“Rather than looking at the amount of dopamine bound on receptors of dopamine-receiving cells, we looked at VMAT2 concentrations within dopamine-producing cells, which may be more sensitive to detecting changes in dopamine with deep brain stimulation in Parkinson’s disease patients.”

Smith and Mills both note that studies on more patients are needed to advance the search for better targets for electrical stimulation so that the brain produces more dopamine and patients reap additional benefits.

The researchers say that increasing dopamine through deep brain stimulation may even help them understand the applications to other psychiatric conditions.

“In the long term we want to have a broader idea of the effects of electric stimulation on brain function and chemistry so that we can better treat Parkinson’s disease and other neurological and psychiatric conditions, like Tourette’s syndrome and depression, which are also affected by the dopamine system,” says Smith.

Parkinson’s disease (PD) is a common neurodegenerative disease, which affects about 1% of the population older than 65 years.1 

It comprises two major neuropathologic findings: the loss of dopaminergic cells of the ventrolateral compartment of the substantia nigra and the presence of Lewy bodies, at least in the brain stem, but with progressive cerebral distribution in the course of the disease.2

Despite the complexity of symptoms in PD, which comprise cognitive and affective dysfunction, as well as sensory and vegetative disturbances, the impairment of motor control (i.e. Parkinsonian syndrome) is still considered as a main clinical feature to make the diagnose.

As such, Parkinsonian syndrome is clinically defined as the presence of bradykinesia in addition to other cardinal symptoms like rigidity, rest tremor, or postural instability.

The progressive loss of dopaminergic neurons may be partially compensated by dopaminergic substitutive therapy and hence allow for symptom control, especially for motor symptoms.

However, medical treatment becomes challenging in the course of the disease due to the development of motor fluctuations, the presence of therapy refractory motor symptoms, or the adverse effects of medical treatment.

Even before the establishment of dopaminergic treatment regimens for PD, neurosurgical procedures of basal ganglia have been considered to treat PD motor symptoms.3 

Because of complication rates, especially with bilateral procedures, pharmacological advances in terms of the availability of levodopa as an effective drug for PD almost completely replaced surgical treatment.4 

While improvement of PD tremor using high frequency thalamic stimulation was already described in 1963, Irvine Cooper was the first who utilized chronic deep brain stimulation (DBS) for sustained tremor control.

Finally, the work of Benabid and colleagues paved the way for DBS for worldwide applications (initially in clinical studies and later in clinical routine) and hence revitalized the application of neurosurgical procedures more than 30 years ago.5 Following encouraging experiences with thalamic DBS, the insights of basal ganglia involvement in the pathophysiology of PD, DBS of the subthalamic nucleus (STN) in particular but also the globus pallidus internus (GPI) was suggested and eventually successfully applied as targets for DBS.6,7 

In contrast to lesioning techniques of pallidofugal fibers or thalamic areas, advantages of DBS are adaptability, reversibility, less tissue damage, and the option to perform bilateral surgery without a significant increase of adverse effects.

Nowadays, DBS has turned into one of the most successful treatment strategies in advanced stages of the disease. In recent years, cutting-edge features of both the implantable pulse generators (IPGs) and the DBS electrodes have been introduced, which increase the degrees of freedom to customize DBS settings and hence optimize the efficacy of treatment. This review summarizes the procedural standards in DBS for PD and how to optimally utilize recent technical advances in clinical practice.

Current state (STN DBS)

Indications and patient selection

Among different available targets, the STN is predominantly selected in the clinical standard of PD care, even though comparative analyses do not indicate superiority towards the second most common target, the GPI.

However, since scientific literature describing observations of DBS in PD is clearly dominated by the STN as the chosen target, this update mainly addresses clinical practice for STN DBS.

Careful selection of applicable patients is one of the hallmarks in avoiding the risk of unsatisfactory outcome following DBS surgery.

As such, only patients suffering from PD, but not secondary or atypical Parkinsonian syndromes, are candidates for DBS surgery. PD itself predominantly comprises sporadic/idiopathic forms, which are most likely caused by polygenic and environmental factors, but also monogenic forms of PD, which are estimated to represent <10% of PD cases.8 

While current data do not allow for robust statements about the efficacy in single monogenic forms of PD, studies with small patient sizes on monogenic PD patients reported good responses to DBS and a considerable percentage of PD patients who undergo DBS may incidentally suffer from monogenic forms of PD anyway.9 

We propose that while clinical hallmarks such as rather aggressive disease progression in patients with GBA gene mutations should kept in mind, patients with (known) monogenic forms of PD may be considered as candidates for DBS, similar to patients suffering from idiopathic PD.

Current German guidelines recommend that the following criteria are mandatory to consider DBS in PD:

(a) presence of motor fluctuations including levodopa-sensitive off symptoms or treatment-induced dyskinesia;

(b) tremor, which cannot be satisfactorily treated with medication;

(c) a levodopa-induced reduction of motor symptoms by >33% of the Unified Parkinson Disease Rating Scale (UPDRS), where tremor may be disregarded from the calculation as it may be refractory to levodopa treatment while still responding well to DBS; and

(d) exclusion of dementia, relevant psychiatric or somatic comorbidity, or general contraindication to undergo neurosurgical interventions.10 

Even more restrictive inclusion criteria are recommended for patients not older than 60 years and the presence of motor fluctuations for not longer than 3 years.10

However, clinicians have to keep in mind that such a restrictive selection of DBS candidates may be problematic, as discussed in the following: excellent response to dopaminergic treatment, a lower degree of levodopa-refractory symptoms, and a younger age increase the likelihood of highly efficacious DBS treatment.11 

As such, a levodopa-induced reduction of motor symptoms by >30% of the UPDRS motor score has been suggested as criterion to identify optimal candidates for surgery.12 Recent studies however, question the value of initial degree of levodopa response to predict a sustained DBS improvement on motor symptoms or quality of life (QOL) measurements.13,14

Several studies indicated that a high biological age is associated with less efficacy15 and a reduced QOL improvement16 following DBS surgery. Additionally, an increased intraoperative risk has been controversially discussed.17,18 However, age was not identified to be an independent factor to influence motor improvement in randomized controlled trials,19 and the risk of surgical complications is rather increased by comorbidities, for which age is a surrogate.20 So far, there is no established threshold as to whether elderly patients are candidates for DBS.

Severe comorbidities which do not allow patients to undergo DBS surgery as well as relevant psychiatric conditions, such as acute psychosis, major depression, or dementia, are generally considered as exclusion criteria.10 

With regard to dementia, surgery may be associated with an increased risk to safely seed the electrodes (due to cerebral atrophy) and postoperative delirium, including persistent deterioration of cognitive and psychological functionality. Hence, current guidelines state that DBS surgery in patients with dementia is contraindicated.10

Additionally, PD dementia frequently manifests at an advanced stage of disease, which is often accompanied by axial symptoms that predominantly contribute to the burden of the disease but may be refractory to DBS.

However, DBS has been shown to be efficacious in patients with mild cognitive impairment,21 and established screening parameters such as the Mattis Dementia Rating Scale alone may not be suitable to predict QOL or motor outcomes after DBS,22 even if cognitive scales were below the threshold for dementia. Therefore, both a careful medical and extensive neuropsychological evaluation not exclusively relying on screening tests is mandatory before the final decision of applicability for DBS.

Finally, structural magnetic resonance imaging (MRI) of the brain is needed for precise planning of a safe trajectory of the DBS electrodes. Additionally, it allows the ruling out of cerebral conditions associated with an increased risk during brain surgery, such as relevant atrophy, or highly vascularized structures.

As outlined above, clinical criteria suggested for identification of DBS candidates cannot precisely predict the outcome of DBS. As a consequence, there cannot be a dichotomous criterion for a clinician to either recommend or deny DBS surgery. Hence, such recommendations for patient selection may rather provide a guide for patient selection but cannot be regarded as strict cutoff parameters.

Furthermore, clinical outcomes can be assessed as measurable scales and values in clinical studies for statistical analyses. But from an individual patient’s perspective, the outcome of DBS surgery may be perceived as beneficial even if objective evaluation would reveal just a very mild response.

Therefore, patients and healthcare providers together should discuss on an individual basis, what patients expect from DBS and if presumable benefits outweigh the risks of DBS surgery. Finally, shared decision-making with the patient is warranted, since only the patient or the legal guardian can know, which benefit–risk ratio is acceptable for them to undergo such a procedure.

More information: Gwenn S. Smith et al. Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson’s disease, Parkinsonism & Related Disorders (2019). DOI: 10.1016/j.parkreldis.2019.04.006

Journal information: Parkinsonism and Related Disorders
Provided by Johns Hopkins University


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