Deep-Brain-Stimulation (DBS) Treatment for Parkinson's Disease

Treating PD with DBS
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Standard equipment used for DBS.

Parkinson's disease (PD) is a neurodegenerative disease that currently has no known cure. The treatment for PD aims to reduce the severity of the motor symptoms, and generally involves a multi-faceted approach to improve the quality of life for patients in both social and medical aspects as PD is chronic and debilitating.
The first steps in treating PD involve a pharmacologic intervention that often relies on a mix of drugs to alleviate the motor deficits. These drugs act on the dopaminergic system of neurons, and are usually dopamine precursors, dopamine agonists or MAO-B inhibitors[1]. Levodopa is a dopamine precursor that is widely used because of its effectiveness, but prolonged usage leads to reduced effectiveness and the emergence of dyskinesia. When the patient begins to exhibit the Levodopa side-effects, surgical techniques are often relied on to relieve the motor symptoms from both PD and the drug treatment[2].
Surgically implanting electrodes for deep-brain stimulation (DBS) relieves almost all parkinsonian symptoms for PD patients who can no longer handle their medication, and is preferred over ablative procedures [2].

1.1 Introduction

DBS has been used in clinical practice since the 1960’s, and its use has gained much clinical acclaim as techniques and technology have improved[2]. The thalamus and globus pallidus interna (GPi) were common targets at the inception of the procedure, but the subthalamic nucleus (STN) has since then emerged as the best target in terms of effectiveness in relieving the symptoms. DBS does not eliminate the need for pharmaceutical treatment of PD, but it reduces the dosage required[3]. This reduction in dosage diminishes the side-effects associated with the drugs. Like the drug treatments, DBS does not cure PD. It does, however, significantly improve the quality of life for the majority of patients and the procedure has been steadily gaining popularity.
Despite its wide clinical use, the underlying mechanism by which DBS works is poorly understood[3]. The electric stimulation is thought to disrupt abnormal neuronal activity that occurs with PD neuronal degeneration. Studies on DBS have mostly focused on its clinical efficacy, but there has been an increasing amount of work concerning the biology behind its effects.

1.2 Surgical Procedure and Equipment

Monitoring electrode implant location during surgery
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Both CT and MRI are useful in accurately placing the 
electrode to target the desired area.  
Image retrieved from people.vriginia.edu

Patients undergo a surgical procedure to have the necessary hardware implanted for DBS. Surgery is performed under local anaesthesia with the guidance of CT or MRI in conjunction with monitoring of neural activity[4]. The surgery is performed in two stages; the initial phase involves placing the electrode leads while the second involves the implantation of pulse generator and extension wires[5]. The implanted pulse generator (IPG) is generally implanted under the collarbone, and the extension wires connecting it to the lead are usually placed subcutaneously. The system operates much like a cardiac pacemaker, and the programming for frequency and magnitude varies for each patient, and can be adjusted later[2]. This postoperative adjustment takes about 40 hours on average to achieve optimal settings. As with any surgically implanted electrical hardware, complications with infection and equipment failure may arise, and are not uncommon[5].

1.3 Clinical Studies of the Efficacy of DBS

Before the focus shifted to elucidating the biological mechanisms, much attention was given to the clinical effectiveness of the treatment itself.

1.3a Patient Prognosis

The effects of DBS on a PD patient (before/after)
This video demonstrates the dramatic improvement seen post-op for a PD patient who underwent surgery for DBS.

The prognosis for patients who undergo surgical treatment for DBS is generally positive [6]. A meta-analysis of twenty-two studies looking at a total of thirty-seven cohorts published in 2006 reviewed the effectiveness of STN DBS. It was found that medication in the form of Levodopa or its equivalents was, on average, reduced by 56% after the procedure. This came in tandem with an average reduction of 69.1% of dyskinesic symptoms (medical side-effect) for the patients, based on rating scales and patient diaries. PD patients typically go through periods of on and off cycles throughout the day. On cycles are associated with minimal PD symptoms and a clarity of mind, while off cycles is associated with the resurfacing of the PD symptoms. The review found that the duration of these off cycles of patients after surgical intervention was reduced by 68.2%. Using PDQ-39, an index for measuring the quality of life for PD patients, an average improvement of 34.5% was found for the cohorts studied.

A study published in 2005 observed the long-term effects of STN DBS in patients with advanced PD at a minimum of four years after surgery [7]. Initial improvements in both on and off motor states observed three-months post-surgery were significantly less profound in the studied population at four-years, decreasing from 42.3% to 24.2%. It was concluded that despite this decrease, which was likely associated with the progression of the disease itself, STN DBS still provides a significant improvement justifying surgical intervention.

1.3b DBS Side-effects

Large-scale analyses have found adverse side-effects possibly associated with the STN DBS treatment, as it is normally absent in medication-only patients [6] [7]. The majority of these are behavioural and cognitive in nature, including hypersexuality, emotional instability, psychosis, and hallucinatory episodes [6]. In about a third of these cases, misdirected stimulation due to inaccuracies in electrode placement was attributed as the cause. Some patients were also found to have a very fine threshold capacity for DBS having either a therapeutic or adverse effect.
A study following 1398 patients published in 2006 found depression to occur in 8% of STN DBS patients, and hypomania in 4% [8]. Anxiety disorders and overall personality changes were comparably rarer. Due to the possibility of these adverse side-effects, a risk/benefit evaluation is suggested for patients considering STN DBS treatment.

1.3c Neuroprotective effects of DBS

Animal models for DBS research
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Animal models provide greater levels of manipulation
that would not be possible with human patients.
Original uploader was Vdegroot at nl.wikipedia.

STN DBS treatment for PD patients has been shown to be effective in maintaining a significant long-term improvement in tremor, rigidity, bradykinesia and medication-related dyskinesias [9]. The treatment, however, is often given to patients in advanced stages of PD. It has been suggested by some that the procedure should be considered earlier in the course of the disease for earlier benefits.

A recent study using a rat model for STN DBS looked at how the treatment affected the progression of PD [10]. Based on previous studies that showed STN DBS stopping neurotoxin-induced degeneration of the unharmed brain, the study analyzed the effects of the treatment in a model brain in a state representative of a patient at the time of PD diagnosis. Brain health conditions were monitored prior and throughout STN DBS treatment, and results were compared to a control group that did not receive treatment. It was found that STN DBS almost completely stopped the progression of neuronal degeneration. The overall brain state appeared to be preserved from the time treatment was initiated. The authors concluded that this should increase the consideration for an earlier timetable of surgical intervention, so the progression of PD can be delayed at a timepoint when there are more neurons preservable from degeneration. A similar neuroprotective effect was observed in another study using primates [11].

Observations from human cases of the attenuation of PD-related neurodegeneration have been mixed, with no conclusive evidence [12]. The lack of a proper randomized study concerning these possible effects of STN DBS can be largely attributed to the fact that patients only undergo surgical procedure at later stages of PD. A recent study (2012) observing the effects of DBS in early treatment for PD is currently in its initial stages, and so far has only reported on the operative experiences [13].

2.1 The Brain Pathways of Parkinson's Disease

A comparison of brain pathways between healthy and PD states
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The size of the arrows indicate the strength of the signaling. Adapted from Smith et al. 2012.

The motor symptoms of PD are the result of idiopathic cell death of the dopaminergic neurons of the substantia nigra pars compacta (SNc), a region in the midbrain [14]. This neurodegeneration causes the depigmentation of the SNc observed in PD patients. The pathways affected in PD are mostly in the basal ganglia. The DA neurons of the SNc project mostly to the dorsolateral putamen, thus the DA depletion is the most severe there in PD brains. Not all nigrostriatal neurons are as affected, however, as DA neurons of the VTA are left mostly intact with significnalty less DA depletion at their projection site in the caudate. Since the SNc is responsible for modifying basal ganglia output in coordination, its signalling absence leads to the difficulty in the initiation and execution of movement seen in PD, as well as the muscle rigidity and resting tremors. The STN, the target for DBS treatment, normally serves to modulate the activity of the GPi and substantia nigra reticulata (SNr) responsible for the inhibition of unwanted movements [15]. The SNc DA neurons serve to inhibit this pathway, thus disinhibiting motor neurons [16].

2.2 Current Models for how DBS works

Many mechanisms for DBS have been proposed, but very little has been elucidated. Complications exist due to the fact that the electrical stimulation of a point target can influence many upstream and downstream pathways [3]. The effects observed in a PD patient undergoing treatment is thought to be the sum of these events, with many interactions between them.

2.2a Stimulatory and Inhibitory Effects of DBS

STN DBS is thought to reduce PD motor symptoms through the moduation of GPi and SNr activity[15]. STN DBS has been shown to cause electrical signals detectable at the scalp, suggesting the activation of neurons [3]. Whether this signal has any clinical relevance is still unknown. More studies have looked at the inhibitory effects of STN DBS, and how long trains of simulation can cause long-lasting periods of neuronal silence. The mechanism by which this silence is induced is unclear, but neural exhaustion or secondary synaptic failure have been suggested as possible explanations. Currently depolarising block and neural fatigue appear to be the most parsimonious explanations, but many factors are in need of examination.

2.2b Functional Imaging Studies

PET and fMRI are the most commonly used imaging techniques in assessing the effects of DBS in human patients [3]. Stimulation of the STN has been observed to increase activation of the ipsilateral rostral supplementary motor area and premotor cortex (for contralateral movement). STN stimulation also reduces cerebral blood flow in the resting primary motor cortex. These findings agree with the model that the disruption of STN and GPi projections through the degeneration of SNc causes much of the pathophysiology of PD. DBS appears to inhibit this pathological output in reducing motor impairment. It is clear, however, that DBS acts through distinct neuronal pathways dependent on electrode placement[17].

2.2c Pathological Synchronized Neuronal Oscillations

It has been noted that the effectiveness of STN DBS is dependent on the stimulation frequency, with high frequencies (>90Hz) improving motor systems [18]. Lower frequencies (<50Hz) tend to be ineffective or make the motor symptoms worse. A study using a rat model of PD was able to show that higher frequency stimulations may be able to entrain firing patterns of the GPe and SNr to the stimulation frequency, thus keeping it from hiring at the low pathological PD frequencies. This is a promising indication that disrupting the low-frequency oscillations between the SNr and GPe, and forcing it to fire at a different rate alleviates PD symptoms. It is interesting that the GPe normally inhibits the STN, causing less activity in the SNr-GPi pathway that inhibits unwanted muscle movement[15]. This would prevent the emergence of the hypokinetic state associated with PD, where the Snr-GPi axis is overactive due to a lack of modulation from the dopaminergic SNc neurons[16]. These findings agree with the prominent model that STN DBS reduces activity from the SNr-GPi pathway, but there is much unexplained.

2.2d Difficulties in Studying DBS

Animal models and brain slice experiments are useful but can often be contradictory due to the nature of the study designs and techniques [3].  DBS electrode types used clinically differ from the ones used in most animal studies, having a much larger contact surface than experimentally used microelectrodes.  This makes target accuracy an issue and complicates comparison between studies.

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