Deep Brain Stimulation
Treatment of Parkinson’s Disease
Sam Park
Brief History

Basal ganglia have been targeted for neuromodulation surgery
since the 1930s.

1950s: Pallidotomy was the accepted procedure for the
treatment of PD.

1960s: Levodopa therapy was introduced
- However, many PD patients remain disabled despite best
available dopaminergic treatment

Limitations of dopaminergic therapy led to a resurgence of new
surgical techniques directed at basal ganglia targets in late
1980s, early 1990s.
Brief History

1993: Bilateral high-frequency stimulation of subthalamic
nucleus (STN) introduced in treatment of advanced PD
- Based on new insights into the pathophysiology of basal ganglia derived from
experimentation on animal models of PD

Siegfried & Lippitz (1994): Introduced DBS of globus pallidus
internus (GPi) for treatment of advanced PD

Pioneering studies & empirical observations during surgery
showed that DBS improved PD patient’s motor function and
quality of life.

Today, DBS (electrical stimulation of basal ganglia structures via
implanted electrodes) has become a non-lesioning alternative
to pallidotomy.
Relevant Brain Structures
Motor Circuit
Parkinson’s Disease
Intervention
Patient Selection



Goal: Find ideal patients, where individual benefit > risk of
surgery
Advanced idiopathic PD with motor complications is main
indication for DBS in PD
Multidisciplinary approach:
1. Neurosurgeon
2. Neurologist
3. Neuropsychologist
Intervention
Patient Selection






Response to levodopa = best prognostic indicator for DBS
suitability
Neuropsychological evaluation
- Depression
- Psychosis
Age
Full medical assessment
Discussion of long-term and short-term effects of DBS
Education regarding environmental concerns with
implantable devices
Intervention
Surgical Procedure


Precise implantation of stimulation electrode
in targeted brain area.
Connecting electrode to internal
programmable pulse generator
Neurobiology
Brain areas targeted in DBS:
1.
2.
3.
Vim = ventralis intermedius nucleus of the
thalamus
GPi = posteroventral portion of the internal
segment of the globus pallidus
STN = subthalamic nucleus
Intervention
Pre-Operative Stage:

Stereotactic Surgery
-
Locate targeted brain areas
Stereotactic frame
MRI, CT, or ventriculography
Stereotactic atlas
Intervention
Pre-Operative Stage:

Functional Stereotactic
Surgery
- Electrophysiological exploration
of targeted regions via test
electrodes
- Involves:
1. Microrecording
2. Test-stimulation
- Increases accuracy of localization
(i.e. finding optimum target in GPi
or STN)
- Under local anesthesia
Intervention

Optimal Stimulation Sites:
- Dorsolateral STN border
- Posteroventral GPi
Implantation of Electrode:


DBS electrode stereotactically inserted with special rigid
guide tube
Patient is awake and in the medication-“off” state after
12-hour withdrawal
Intervention
Implantation of Electrode:


Electrode has 4 contacts
on its distal end
The effects of
stimulation from each
combination of 2
contacts or monopolarly
from each contact are
assessed
- Determine best
contact(s) to use to
obtain optimal
therapeutic benefit
Intervention
Electrode-Stimulator Connection:



Electrode  Extension (passed
under skin to chest)  Chest:
Battery-operated stimulator
Patient turns stimulator “on” and
“off” by passing magnet over the
skin overlying stimulator
Typical stimulator settings:
- Voltage amplitude: 2-3 V
- Pulse width: 90 μs
- Stimulation frequency: 130-185
Hz
Intervention
Electrode-Stimulator Connection:


Stimulator parameters
adjusted via a computercontrolled probe placed over
stimulator
Pulse generator can be
adjusted post-operatively by
telemetry:
(1) Electrode configuration,
(2) Voltage amplitude
(3) Pulse width
(4) Frequency
Mechanisms of DBS

The exact mechanisms underlying the
beneficial effects of DBS are still unknown.

Logistical fallacy exists.

Many hypotheses exist regarding the
mechanisms underlying high-frequency
stimulation.
Mechanisms of DBS
1. HFS may inhibit neurons



Synaptic depression by stimulation-induced neurotransmitter
depletion.
STN HFS suppresses STN neuronal activity
Effects of microstimulation on firing of
neurons in GPi:
- Single, low-intensity stimuli in GPi
produced inhibition of GPi neuronal
firing rate
- High-frequency, low-intensity trains
of stimuli caused periods of inhibition
- Synaptic inhibition by stimulation of
inhibitory afferents to GPi
Mechanisms of DBS
2. HFS may excite neurons


A subthreshold normal signal, lost in the noise of a deranged
neural network, is amplified by the addition of a regular noise
(HFS).
“Jamming” of information
- Constant high-frequency excitation may disrupt any
pathophysiological patterns of neuronal activity
- Excitation may lead to desensitization or other long-term
changes in pre-/post-synaptic excitability of GPi synapses
Mechanisms of DBS
3. HFS of STN neurons may lead to
hyperpolarization



Due to activation of Ca2+-dependent K+ currents
Prolonged HFS in rat STN caused prolonged inactivation of
volatage-gated Na2+ and Ca2+ channels
Similar mechanisms might exist in GPi neurons
4. Depolarization block


HFS causes cell to fire, without sufficient time to repolarize
the membrane potential
Neuronal transmission blocked and firing rates decreased
Deuschl et al. (2006) Study
A Randomized Trial of Deep-Brain Stimulation of
Parkinson’s Disease
Design:




Unblinded, randomized-pairs trial
Participants: 156 patients with advanced Parkinson’s disease
and severe motor symptoms
Participants were randomly assigned to 2 groups:
1. Deep-brain stimulation of subthalamic nucleus (STN)
2. Best medical treatment
Primary end points: Changes from baseline to 6 months
Measures:


Quality of life = Parkinson’s Disease Questionnaire (PDQ-39)
Severity of motor symptoms, without medication = Unified
Parkinson’s Disease Rating Scale, part III (UPDRS-III)
Deuschl et al. (2006) Study
A Randomized Trial of Deep-Brain Stimulation of
Parkinson’s Disease
Results:
Mean PDQ-39 Summary Index Score:
Baseline
Neurostimulation
Group
Medication Group



6 months
41.8 ± 13.9 31.8 ± 16.3
39.6
40.2 ± 14.4
Neurostimulation Group: Mean improvements of 9.5 points
(25% improvement) from baseline to 6 months
Medication Group: No change
Neurostimulation resulted in improvements of 24%-38% in
PDQ-39 subscales for mobility, activities of daily living,
emotional well-being, stigma, and bodily discomfort.
Deuschl et al. (2006) Study
A Randomized Trial of Deep-Brain Stimulation of
Parkinson’s Disease
Results:
Mean UPDRS-III Score:
Neurostimulation
Group
Medication Group


Baseline
6 months
48.0
28.3 ± 14.7
46.8 ± 12.1 46.0 ± 12.6
Neurostimulation Group: Mean improvements of 19.6
points (41% improvement) from baseline to 6 months
Medication Group: No change
Deuschl et al. (2006) Study
A Randomized Trial of Deep-Brain Stimulation of
Parkinson’s Disease
Conclusion:


Subthalamic neurostimulation was more effective than
medical management alone for the treatment of patients with
advanced Parkinson’s
Serious adverse events were more common with
neurostimulation than with medication alone
- Intra-cerebral hemorhage
Limitations:

No sham-surgery or placebo control groups used
Schüpbach et al. (2005) Study
Stimulation of the Subthalamic Nucleus in Parkinson’s
Disease: a 5 Year Follow Up
Design:



5 year follow up study
Participants: 37 patients with PD, treated with bilateral STN
stimulation
Participants assessed prospectively 6, 24, and 60 months after
surgery
Measures:



Motor assessment: UPDRS-III
Activities of daily living: UPDRS-II
Neuropsychological and mood assessment: Mattis Dementia
Rating Scale, the frontal score, Montgomery-Asberg
Depression Rating Scale (MADRS)
Schüpbach et al. (2005) Study
Stimulation of the Subthalamic Nucleus in Parkinson’s
Disease: a 5 Year Follow Up
Results:
Schüpbach et al. (2005) Study
Stimulation of the Subthalamic Nucleus in Parkinson’s
Disease: a 5 Year Follow Up
Results:
Assessment 5 years after surgery:
 STN stimulation improved activity of daily living by 40% (“off”
levodopa) and 60% (“on” levodopa)
 STN stimulation improved Parkinsonian motor disability by
54% (“off” drug) and 73% (“on” drug)
 Severity of levodopa related motor complications decreased
by 67%
 No change in MADRS
 Cognitive performance declined
Schüpbach et al. (2005) Study
Stimulation of the Subthalamic Nucleus in Parkinson’s
Disease: a 5 Year Follow Up
Adverse Side Effects:


Persisting side effects: eyelid opening apraxia, weight gain,
hypomania and disinhibition, dysarthria
During 60 month follow up, 6 patients died
Limitations:

Absence of a control group
Conclusions:

Long-term post-operative improvement in Parkinsonian motor
disability was sustained 5 years after neurosurgery
Advantages of DBS

Avoid adverse side effects associated with lesioning
procedures

Does not require deliberate destruction of brain regions

Effects of stimulation therapy are reversible
- Due to reversibility, does not preclude use of future
therapies

Can change stimulation parameters to optimize clinical
benefit
Advantages of DBS

Can be safely performed bilaterally (in contrast to
ablative procedures)

May be the only effect treatment of levodopa-induced
dyskinesias

The beneficial changes are long-lasting
Disadvantages of DBS

Adverse side effects related to surgery
- Intra-cranial hemorrhage
- Pulmonary embolism, chronic subdural hematoma, venous infarction,
seizure

Hardware related failure
- Lead extension fracture, lead migration, short or open circuit, malfunction
of pulse generator, infection, etc.

Adverse effects related to electrical stimulation
- Electrical current could spread into adjacent structures,
leading to tonic muscle contraction, dysarthria,
paraesthesia, worsening of akinesia, etc.
Disadvantages of DBS

Post-operative adverse side effects are common
-

Weight gain
Dyskinesia
Axial symptoms
Eyelid, ocular, visual disturbances
Behavioral and cognitive problems (e.g.
- Muscle contractions
- Paresthesia
- Speech dysfunction
mood disorders)
Long-term complications
- Infection or erosion
- Tolerance
- Pain and discomfort
- Sudden loss of effect
- Development of dementia

Costs of surgery

Cannot use sham surgeries as controls
Conclusion


Overall, I feel that DBS is one of the best and most effective
treatment options for advanced Parkinson’s. It is not only safer
than many lesioning procedures, but has been empirically shown
to reduce levodopa-induced symptoms. Longitudinal studies and
randomized control trials have also provided support for its
efficacy.
However, the procedure may not be suitable for every PD patient.
This is especially evident by the careful screening process
involved in patient selection, which attempts to identify patients
with idiopathic PD and motor complications. Additionally, the fact
that the success of the intervention relies heavily on physiological
and psychological factors, the assessment process puts great
emphasis on the neuropsychological function of the disease.
Conclusion

Although the pathophysiology of PD has been well studied and
determined, there are many aspects which are still unknown.
Future research should be directed at the exact mechanisms by
which DBS exerts its beneficial effects. It may be possible that
one of the hypotheses for the mechanism of action already
discussed is in fact correct.