1. Deep Brain Stimulation Sam Park Treatment of Parkinson’s Disease

2. Brief History Basal ganglia have been targeted for neuromodulation surgery since the 1930s. Basal ganglia have been targeted for neuromodulation surgery since the 1930s. 1950s: Pallidotomy was the accepted procedure for the treatment of PD. 1950s: Pallidotomy was the accepted procedure for the treatment of PD. 1960s: Levodopa therapy was introduced 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. Limitations of dopaminergic therapy led to a resurgence of new surgical techniques directed at basal ganglia targets in late 1980s, early 1990s.

3. Brief History Today, DBS (electrical stimulation of basal ganglia structures via implanted electrodes) has become a non-lesioning alternative to pallidotomy. Today, DBS (electrical stimulation of basal ganglia structures via implanted electrodes) has become a non-lesioning alternative to pallidotomy. 1993: Bilateral high-frequency stimulation of subthalamic nucleus (STN) introduced in treatment of advanced PD 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 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. Pioneering studies & empirical observations during surgery showed that DBS improved PD patient’s motor function and quality of life.

4. Relevant Brain Structures Motor Circuit

5. Parkinson’s Disease

6. Intervention Patient Selection Goal: Find ideal patients, where individual benefit > risk of surgery Goal: Find ideal patients, where individual benefit > risk of surgery Advanced idiopathic PD with motor complications is main indication for DBS in PD Advanced idiopathic PD with motor complications is main indication for DBS in PD Multidisciplinary approach: Multidisciplinary approach: 1. Neurosurgeon 2. Neurologist 3. Neuropsychologist

7. Intervention Patient Selection Response to levodopa = best prognostic indicator for DBS suitability Response to levodopa = best prognostic indicator for DBS suitability Neuropsychological evaluation Neuropsychological evaluation - Depression - Psychosis Age Age Full medical assessment Full medical assessment Discussion of long-term and short-term effects of DBS Discussion of long-term and short-term effects of DBS Education regarding environmental concerns with implantable devices Education regarding environmental concerns with implantable devices

8. Intervention Surgical Procedure Precise implantation of stimulation electrode in targeted brain area. Precise implantation of stimulation electrode in targeted brain area. Connecting electrode to internal programmable pulse generator Connecting electrode to internal programmable pulse generator

9. Neurobiology Brain areas targeted in DBS: 1. Vim = ventralis intermedius nucleus of the thalamus 2. GPi = posteroventral portion of the internal segment of the globus pallidus 3. STN = subthalamic nucleus

10. Intervention Pre-Operative Stage: Stereotactic Surgery Stereotactic Surgery - Locate targeted brain areas - Stereotactic frame - MRI, CT, or ventriculography - Stereotactic atlas

11. Intervention Pre-Operative Stage: Functional Stereotactic Surgery Functional Stereotactic Surgery - Electrophysiological exploration of targeted regions via test electrodes - Involves: 1. Microrecording 1. Microrecording 2. Test-stimulation 2. Test-stimulation - Increases accuracy of localization (i.e. finding optimum target in GPi or STN) - Under local anesthesia

12. Intervention Optimal Stimulation Sites: Optimal Stimulation Sites: - Dorsolateral STN border - Posteroventral GPi DBS electrode stereotactically inserted with special rigid guide tube DBS electrode stereotactically inserted with special rigid guide tube Patient is awake and in the medication-“off” state after 12-hour withdrawal Patient is awake and in the medication-“off” state after 12-hour withdrawal Implantation of Electrode:

13. Intervention Electrode has 4 contacts on its distal end 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 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 Implantation of Electrode:

14. Intervention Electrode  Extension (passed under skin to chest)  Chest: Battery-operated stimulator 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 Patient turns stimulator “on” and “off” by passing magnet over the skin overlying stimulator Typical stimulator settings: Typical stimulator settings: - Voltage amplitude: 2-3 V - Pulse width: 90 μs - Stimulation frequency: 130-185 Hz Electrode-Stimulator Connection:

15. Intervention Stimulator parameters adjusted via a computer- controlled probe placed over stimulator Stimulator parameters adjusted via a computer- controlled probe placed over stimulator Pulse generator can be adjusted post-operatively by telemetry: Pulse generator can be adjusted post-operatively by telemetry: (1) Electrode configuration, (2) Voltage amplitude (3) Pulse width (4) Frequency Electrode-Stimulator Connection:

16. Mechanisms of DBS The exact mechanisms underlying the beneficial effects of DBS are still unknown. The exact mechanisms underlying the beneficial effects of DBS are still unknown. Logistical fallacy exists. Logistical fallacy exists. Many hypotheses exist regarding the mechanisms underlying high-frequency stimulation. Many hypotheses exist regarding the mechanisms underlying high-frequency stimulation.

17. Mechanisms of DBS 1. HFS may inhibit neurons Synaptic depression by stimulation-induced neurotransmitter depletion. Synaptic depression by stimulation-induced neurotransmitter depletion. STN HFS suppresses STN neuronal activity STN HFS suppresses STN neuronal activity Effects of microstimulation on firing of neurons in GPi: 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

18. 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). 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 “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

19. Mechanisms of DBS 3. HFS of STN neurons may lead to hyperpolarization Due to activation of Ca 2+ -dependent K + currents Due to activation of Ca 2+ -dependent K + currents Prolonged HFS in rat STN caused prolonged inactivation of volatage-gated Na 2+ and Ca 2+ channels Prolonged HFS in rat STN caused prolonged inactivation of volatage-gated Na 2+ and Ca 2+ channels Similar mechanisms might exist in GPi neurons Similar mechanisms might exist in GPi neurons 4. Depolarization block HFS causes cell to fire, without sufficient time to repolarize the membrane potential HFS causes cell to fire, without sufficient time to repolarize the membrane potential Neuronal transmission blocked and firing rates decreased Neuronal transmission blocked and firing rates decreased

20. Deuschl et al. (2006) Study Design: Unblinded, randomized-pairs trial Unblinded, randomized-pairs trial Participants: 156 patients with advanced Parkinson’s disease and severe motor symptoms Participants: 156 patients with advanced Parkinson’s disease and severe motor symptoms Participants were randomly assigned to 2 groups: 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 Primary end points: Changes from baseline to 6 months A Randomized Trial of Deep-Brain Stimulation of Parkinson’s Disease Measures: Quality of life = Parkinson’s Disease Questionnaire (PDQ-39) 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) Severity of motor symptoms, without medication = Unified Parkinson’s Disease Rating Scale, part III (UPDRS-III)

21. Deuschl et al. (2006) Study Results : Mean PDQ-39 Summary Index Score: A Randomized Trial of Deep-Brain Stimulation of Parkinson’s Disease Baseline 6 months Neurostimulation Group 41.8 ± 13.9 31.8 ± 16.3 Medication Group 39.6 40.2 ± 14.4 Neurostimulation Group: Mean improvements of 9.5 points (25% improvement) from baseline to 6 months Neurostimulation Group: Mean improvements of 9.5 points (25% improvement) from baseline to 6 months Medication Group: No change 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. Neurostimulation resulted in improvements of 24%-38% in PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort.

22. Deuschl et al. (2006) Study Results : Mean UPDRS-III Score: A Randomized Trial of Deep-Brain Stimulation of Parkinson’s Disease Baseline 6 months Neurostimulation Group 48.0 28.3 ± 14.7 Medication Group 46.8 ± 12.1 46.0 ± 12.6 Neurostimulation Group: Mean improvements of 19.6 points (41% improvement) from baseline to 6 months Neurostimulation Group: Mean improvements of 19.6 points (41% improvement) from baseline to 6 months Medication Group: No change Medication Group: No change

23. Deuschl et al. (2006) Study A Randomized Trial of Deep-Brain Stimulation of Parkinson’s Disease Limitations: No sham-surgery or placebo control groups used No sham-surgery or placebo control groups used Conclusion: Subthalamic neurostimulation was more effective than medical management alone for the treatment of patients with advanced Parkinson’s 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 Serious adverse events were more common with neurostimulation than with medication alone - Intra-cerebral hemorhage

24. Sch ü pbach et al. (2005) Study Design: 5 year follow up study 5 year follow up study Participants: 37 patients with PD, treated with bilateral STN stimulation Participants: 37 patients with PD, treated with bilateral STN stimulation Participants assessed prospectively 6, 24, and 60 months after surgery Participants assessed prospectively 6, 24, and 60 months after surgery Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: a 5 Year Follow Up Measures: Motor assessment: UPDRS-III Motor assessment: UPDRS-III Activities of daily living: UPDRS-II Activities of daily living: UPDRS-II Neuropsychological and mood assessment: Mattis Dementia Rating Scale, the frontal score, Montgomery-Asberg Depression Rating Scale (MADRS) Neuropsychological and mood assessment: Mattis Dementia Rating Scale, the frontal score, Montgomery-Asberg Depression Rating Scale (MADRS)

25. Sch ü pbach et al. (2005) Study Results: Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: a 5 Year Follow Up

26. Sch ü pbach et al. (2005) Study Results: Assessment 5 years after surgery: STN stimulation improved activity of daily living by 40% (“off” levodopa) and 60% (“on” levodopa) 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) STN stimulation improved Parkinsonian motor disability by 54% (“off” drug) and 73% (“on” drug) Severity of levodopa related motor complications decreased by 67% Severity of levodopa related motor complications decreased by 67% No change in MADRS No change in MADRS Cognitive performance declined Cognitive performance declined Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: a 5 Year Follow Up

27. Sch ü pbach et al. (2005) Study Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: a 5 Year Follow Up Conclusions: Long-term post-operative improvement in Parkinsonian motor disability was sustained 5 years after neurosurgery Long-term post-operative improvement in Parkinsonian motor disability was sustained 5 years after neurosurgery Limitations: Absence of a control group Absence of a control group Adverse Side Effects: Persisting side effects: eyelid opening apraxia, weight gain, hypomania and disinhibition, dysarthria Persisting side effects: eyelid opening apraxia, weight gain, hypomania and disinhibition, dysarthria During 60 month follow up, 6 patients died During 60 month follow up, 6 patients died

28. Advantages of DBS Avoid adverse side effects associated with lesioning procedures Avoid adverse side effects associated with lesioning procedures Does not require deliberate destruction of brain regions Does not require deliberate destruction of brain regions Effects of stimulation therapy are reversible Effects of stimulation therapy are reversible - Due to reversibility, does not preclude use of future therapies Can change stimulation parameters to optimize clinical benefit Can change stimulation parameters to optimize clinical benefit

29. Advantages of DBS Can be safely performed bilaterally (in contrast to ablative procedures) Can be safely performed bilaterally (in contrast to ablative procedures) May be the only effect treatment of levodopa-induced dyskinesias May be the only effect treatment of levodopa-induced dyskinesias The beneficial changes are long-lasting The beneficial changes are long-lasting

30. Disadvantages of DBS Adverse side effects related to surgery Adverse side effects related to surgery - Intra-cranial hemorrhage - Pulmonary embolism, chronic subdural hematoma, venous infarction, seizure Adverse effects related to electrical stimulation Adverse effects related to electrical stimulation - Electrical current could spread into adjacent structures, leading to tonic muscle contraction, dysarthria, paraesthesia, worsening of akinesia, etc. Hardware related failure Hardware related failure - Lead extension fracture, lead migration, short or open circuit, malfunction of pulse generator, infection, etc.

31. Disadvantages of DBS Post-operative adverse side effects are common Post-operative adverse side effects are common - Weight gain- Muscle contractions - Dyskinesia- Paresthesia - Axial symptoms- Speech dysfunction - Eyelid, ocular, visual disturbances - Behavioral and cognitive problems (e.g. mood disorders) Long-term complications Long-term complications - Infection or erosion- Tolerance - Pain and discomfort- Development of dementia - Sudden loss of effect Costs of surgery Costs of surgery Cannot use sham surgeries as controls Cannot use sham surgeries as controls

32. 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. 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. 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.

33. 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. 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.