The Placebo Response and Effect  Can be significant  30% or more in certain interventions  An individual’s overall disease manifestation and treatment outcome is influenced by one’s beliefs, emotional and cognitive status and overall feeling of well-being  The placebo response occurs in patients with  Chronic pain, sensory processing  Movement disorders and motor dysfunction  Behavior and mental disorders  Cognitive disorders

The Placebo Effect  The effect is linked to expectation of improvement, Pavlovian conditioning, and other mechanisms  Many neuromodulation studies have resulted in failures when the treatment outcome is compared to placebo  Migraine, stroke, depression, Parkinson’s gene infusion therapies  Parkinson’s STN DBS study demonstrating objective improvement in motor function with the DBS OFF and suggestion to patient being ON

Placebo Effect in Chronic Pain  Neurochemical mechanisms  Endogenous opioid system implicated  The affect can be blocked and reversed by the μ-opioid antagonist (Naloxone)  Higher concentrations of endorphins in in the CSF  Autonomic connections  Placebo analgesia is accompanied by reduced heart rate and decreased β- adrenergic responses  Placebos can also act on 5-HT- dependent hormone secretion  Pituitary and adrenal glands

4 Placebo and Brain Imaging  Increase in cerebral blood flow in the rostral anterior cingulate cortex  Similar outcome as with the administration of opioid receptor agonist (Remifentanil)  (Petrovic et al).

5 Placebo and Brain Imaging  Modulation of the  Insular cortex, thalamus, sensory cortex  Pre-frontal cortex, DLPFC, Orbitofrontal cortex  Similar regions are implicated in  Chronic pain  Anxiety, depression, behavior  Brain regions activated by noxious stimuli were diminished in placebo  Benedetti, Wager, Amanzino, Levine

6 Placebo and Study Trial Design  Comparison to placebo control design  Is the placebo control itself been validated as a true control when there has been an intervention  The neuromodulation implant, the close follow-up monitoring and attention to patients can potentially alter the natural course of the disease and responsiveness  Need more studies comparing neuromodulation intervention to best medical management  Blinding strategies may need to be modified  Cross over design  Longer-term blinded evaluations  How about a non-invasive placebo stimulator as the next big thing in neuromodulation

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Neuromodulation Patient Selection: The Disease The Disease Complex disorders classified by a NAME However these are heterogeneous disorders with pathophysiology, and clinical presentation Movement disorders, epilepsy, chronic pain, psychiatric and cognitive disorders Subtypes and similar presentations are classified and categorized under one disorders Dedicated team of specialists evaluating the patients to verify Diagnosis accuracy and chronicity Co-morbidity variables Treatment resistance and severity Pre-morbid functional status

Neuromodulation Patient Selection: The Chronic Refractory Condition Chronic disease and disability What is considered a disability and how is that determined Will that disability specifically improve with neuromodulation PD-Posture, writing, speech will not improve Is the motor disability worse than the pain Often the most problematic and disabling element of the disease may not be congruent with the symptoms neuromodulation optimally treats Does the neurological examination make sense and correlate with the anatomical lesion Severe tremor that stops with distraction Location of pain

Neuromodulation Patient Selection: When is the right time for Neuromodulation When is the right time for neuromodulation implant What is a refractory patient What is an end stage patient How many meds, how many procedures does the patient need to have before being an “appropriate” candidate Is there a capacity and reserve in the neuronal network to allow for neuromodulation to work optimally When do you consider neuromodulation intervention Early vs. late

Neuromodulation Patient Selection: Previous treatments Previous history of response to medications or treatments is a positive predictor Negative predictors A patient who gets worse with every procedure A patient whose pain migrates with each procedure Multiple procedures A patient had multiple complications and adverse events with each procedure

Neuromodulation: Patient Selection Neuropsychological Screening Psychiatric evaluation No major untreated psychological factors Pain Stress Depression Limited/Loss of Abilities Axis I-depression, anxiety, OCD must be controlled and stable Axis II—Caution--borderline personality dependence or gain

Neuromodulation: Patient Selection Variables Social elements Family and social support systems need to be in place Work situation Patient and family must be cooperative and motivated

Neuromodulation: Patient Selection Variables Clear understanding of the procedure Benefits—SYMPTOMATIC and NOT A CURE Complications must be very clearly understood and repeated Realistic expectations about benefits need to be emphasized Motivated to get better Follow-up with therapy and neuromodulation implant adjustments

Neuromodulation: Patient Selection Variables Adjunctive therapies are important Neuromodulation procedures is one part of an overall integrated rehabilitation strategy  Programming is complex and requires vigilance, monitoring and expertise  Disease fluctuations and progression need to be considered  Initiation of other therapies  Social and occupational changes  Adjustment to life change

Neuromodulation Patient Selection: Biomarkers  Biomarkers are important area of research and necessity to improve patient selection  Imaging  Functional MRI, PET, EEG  Blood test  Genetic screening  TMS  Other physiological markers 16

Neuromodulation: Patient Selection Variables  Neuromodulation can be very effective and improve function and quality of life  However patient selection is:  Not trivial  Need to consider many variables  Evaluation  Clear and detailed understanding of the patient  Multidisciplinary team assessment  Different time points  Team meetings to agree on selection, discussing the overall patient, social status, and follow-up care prior to performing actual procedure 17