1. C LINICAL S TAFF T RAINING P RESENTATION 1 Crystal Blais, Ph.D. Scientific Affairs Liaison Training Program Manager © 2014 Nuraleve, Inc. Proprietary and Confidential. 13-11-2014 SOP-LI-03-57 Rev C

2. Defining Chronic Pain 2

3. Definitions: Pain Pain An unpleasant sensory or emotional experience associated with potential or actual tissue damage, or described in terms of such damage 3 3 © 2014 Nuraleve, Inc. Proprietary and Confidential.

4. Definitions: Nervous System 4 4 © 2014 Nuraleve, Inc. Proprietary and Confidential.

5. Definitions: Nociception 5 5

6. How injury leads to pain Steps: TTransduction: from noxious stimuli at nociceptors to nerve impulses TTransmission: nerve impulses from periphery to CNS PPerception: the experience of pain MModulation: modulation of pain from brain to spinal cord Sensitization – important for chronic pain development Peripheral sensitization: nociceptors generate nerve impulses easier Central sensitization: spinal neuron hyper-excitability 6 6 © 2014 Nuraleve, Inc. Proprietary and Confidential.

7. Classes of pain Acute pain Chronic pain (or chronic non-cancer pain) Cancer pain Acute pain  Occurs in response to tissue trauma  Goes away when injury heals  Serves an important biological function 7 7 © 2014 Nuraleve, Inc. Proprietary and Confidential.

8. Chronic Pain: Definition Chronic pain features:  Pain that persists past the normal time of healing  Pain lasting longer than 12 weeks*  Low levels of underlying pathology that do not explain the presence and/or extent of the pain  Perpetuated by factors remote from the cause  Pain continues to occur (continuous or intermittently) without acute exacerbations A persistent pain that “disrupts sleep and normal living, ceases to serve a protective function, and instead degrades health and functional capability” 8 8 © 2014 Nuraleve, Inc. Proprietary and Confidential.

9. Causes of Chronic Pain  Acute injury (e.g., whiplash)  Chronic conditions (e.g., multiple sclerosis)  In some cases: no discernable cause 9 9 © 2014 Nuraleve, Inc. Proprietary and Confidential.

10. tDCS: How It Works 10

11. Background Transcranial direct current stimulation (tDCS) NNon-invasive technique Administered using scalp electrodes LLow amounts of current (DC) standard dose: 2 mA SStimulates select regions of the brain For chronic pain: m otor cortex (M1) SSession duration: 2 0 minutes 11 © 2014 Nuraleve, Inc. Proprietary and Confidential.

12. Background 12 © 2014 Nuraleve, Inc. Proprietary and Confidential. Two electrodes:  Anode  Cathode anode cathode Current flows from anode to cathode Two methods of stimulation:  Anodal stimulation  Cathodal stimulation

13. Cortical Excitability 13 © 2014 Nuraleve, Inc. Proprietary and Confidential. Anodal stimulation Increased cortical excitability Cathodal stimulation Decreased cortical excitability tDCS changes how our neural circuits respond to stimuli

14. tDCS & Neuromodulation 14 © 2014 Nuraleve, Inc. Proprietary and Confidential. Long-term brain changes via tDCS occur due to: 1. Modulation of neurotransmitter activity glutamate GABA 2. Neuronal excitation Long-term potentiation (LTP) Increased synaptic strength/efficacy 3. Neuroplasticity Functional changes

15. tDCS & Chronic Pain 15 © 2014 Nuraleve, Inc. Proprietary and Confidential. Anodal stimulation of the motor cortex (MI1) results in decreased pain due to:  Decreased processing of pain signals Via suppression of sensory neurons in thalamus  Decreased activity in somatosensory cortex Via direct pathway with M1  Endogenous opioid release

16. tDCS & Chronic Pain 16 © 2014 Nuraleve, Inc. Proprietary and Confidential. Anodal stimulation of the motor cortex (MI1) results in decreased pain due to:  Decreased processing of pain signals Via suppression of sensory neurons in thalamus  Decreased activity in somatosensory cortex Via direct pathway with M1  Endogenous opioid release

17. Safe Use tDCS is safe when applied within standard safety guidelines  Minor adverse events include: Mild tingling sensation Drowsiness Itching/burning Headache Light headedness  No major side effects or serious adverse events have been reported 17 © 2014 Nuraleve, Inc. Proprietary and Confidential.

18. Contraindications Patients may not be eligible for Painrelief if they:  Are under 18 years of age  Have had a recent (<6 months ago) head injury  Have a history of seizures/epilepsy  Have metal embedded in the skull  Have a pacemaker and/or other implanted electrical devices  Have lesions, lipomas, open wounds or bruising on the scalp at the electrode site 18 © 2014 Nuraleve, Inc. Proprietary and Confidential.

19. tDCS & Chronic Pain: Studies 19

20. tDCS & Chronic Pain: Indications Fibromyalgia Migraines Diabetic neuropathy Chronic back pain Trigeminal neuralgia Polyneuropathy Atypical face pain Arthrosis Post-stroke pain Phantom pain 20 © 2014 Nuraleve, Inc. Proprietary and Confidential.

21. tDCS & the Motor Cortex (M1) 21 © 2014 Nuraleve, Inc. Proprietary and Confidential.  Decreased pain intensity  Decreased pain frequency  Decreased pain duration  Improved quality of life  Improved sleep quality Beneficial effects are both acute and long-lasting  Effects seen up to 4 months post-treatment Anodal stimulation of M1 results in:

22. Anodal tDCS of M1: Studies 22 © 2014 Nuraleve, Inc. Proprietary and Confidential.StudyPopulationSampleSizeSessionsEfficacy % Responders Gonçalves et al., 2014 Chronic lower back and/or lower limb pain 205 →80% responders (i.e., reduction of 50% or more in pain intensity) in the active group 80% Kim et al., 2013 Painful diabetic polyneuropathy (PDPN) 605 After 5 th session: →20-50% reduction (from baseline) in pain scores →65% of participants reported ≥30% decrease) →Illness severity decreased (from baseline) 31.5% →Pain reduced up to 4 weeks post-treatment 65% Wrigley et al., 2013 Neuropathic pain due to spinal cord injury 105None10%

23. Anodal tDCS of M1: Studies 23 © 2014 Nuraleve, Inc. Proprietary and Confidential.StudyPopulation Sample Size SessionsEfficacy % Responders DaSilva et al., 2012 Chronic migraine1310 From baseline to 4 months post-stimulation: →migraine intensity: from 4.6 to 2.9 →length of migraine (hrs): from 8 to.9 From baseline to 30 days post-stimulation: →75% of patients saw moderate improvement with partial remission of symptoms 75% Mendonca et al., 2011 Fibromyalgia301NoneN/A Antal et al., 2010 Therapy-resistant chronic pain syndrome 125 After 5 sessions: →63% responders (i.e., reduction of 30% or more in pain intensity) Decrease in pain intensity (change from baseline): →After 5th session: 33.5% →7 days post-study: 11% →14 days post-study: 28% →28 days post-study: 27% 63%

24. Anodal tDCS of M1: Studies 24 © 2014 Nuraleve, Inc. Proprietary and Confidential.StudyPopulation Sample Size SessionsEfficacy % Responders Valle et al., 2009 Fibromyalgia (women only) 4110 Pain scores: values not given Quality of life: →28% improvement Not reported Roizenblatt et al., 2007 Fibromyalgia325 Pain scores: →59% decrease Sleep measures: →decreased arousal: 35% →increased sleep efficacy: 12% Not reported Fregni et al., 2006a Central pain after traumatic spinal injury 175 Pain scores: →After 5 sessions: 58% decrease →During follow-up (16 days post-treatment): 37% 5 sessions: 63% Follow-up: 36% Fregni et al., 2006b Fibromyalgia325 Quality of life scores: →"Pain" item: 49% improvement →Overall quality of life: 36% improvement Not reported

25. tDCS & Chronic Pain: Considerations 25

26. Treatment Outcomes Factors that affect treatment outcomes:  Age  Circadian rhythms  Resting brain states  Hormone levels  Underlying mechanisms of pain Central sensitization 26 © 2014 Nuraleve, Inc. Proprietary and Confidential.

27. The Motor Cortex (M1) The homunculus: 27 © 2014 Nuraleve, Inc. Proprietary and Confidential.

28. tDCS & Painrelief™ 28

29. Painrelief™ Program 29 © 2014 Nuraleve, Inc. Proprietary and Confidential. Chronic pain reduction program:  10 consecutive sessions  20 minutes each  2 mA

30. Painrelief™ System 30 © 2014 Nuraleve, Inc. Proprietary and Confidential.

31. Painrelief™ Accessories  Accessories you will use: Skin markers Measuring tape Alcohol swabs Electrodes & lead wires Sponges Saline solution Electrode prep container Batteries and chargers 31 © 2014 Nuraleve, Inc. Proprietary and Confidential.

32. 32 © 2014 Nuraleve, Inc. Proprietary and Confidential. 32 Determining electrode placement International 10-20 System

33. Determining electrode placement 33 © 2014 Nuraleve, Inc. Proprietary and Confidential. 33 Cathode (right forehead) Anode Anode (left motor cortex) Cathode (left forehead) Anode Anode (right motor cortex) Pain on right side of body Anode Anode : left M1 Cathode : Cathode : right forehead Pain on left side of body Anode : Anode : right M1 Cathode : Cathode : left forehead Pain on both sides of body Anode : Anode : dominant hemisphere

34. 1.Measure head midline from the nasion to the inion, marking 10% ( Fp z ) Determining electrode placement 34 © 2014 Nuraleve, Inc. Proprietary and Confidential. 34 10% Depression between eyes Bump at back of head

35. Determining electrode placement 35 © 2014 Nuraleve, Inc. Proprietary and Confidential. 35 1.Measure head midline from the nasion to the inion, marking 10% ( Fp z ) 2.Align the cap so that the marked point is in the center of the Fp z point.

36. Determining electrode placement 36 © 2014 Nuraleve, Inc. Proprietary and Confidential. 36 1.Measure head midline from the nasion to the inion, marking 10% ( Fp z ) 2.Align the cap so that the marked point is in the center of the Fp z point. 3.Mark the points C3 / Fp 1 (right side pain) and C4 / Fp 2 (left side pain) on the cap Fp 2 Fp 1 C4C3

37. Tips and Tricks Hair:  Split the hair around the target location.  Pre-wet hair if necessary by rubbing the sponge in the target location. Then, re-apply saline on sponge  Use alcohol swab to remove marker dots from scalp at end of session Electrodes: Red electrode: middle should be at exact location, with uniform pressure. Black electrode: the more contact area, the merrier. 37 © 2014 Nuraleve, Inc. Proprietary and Confidential.

38. Tips and Tricks W HAT YOU DON ’ T WANT : Shifting of electrodes (especially red) Shifting of electrode  during initial installation  at any point during the session will result in stimulation of an incorrect brain region Prevention:  Adjust electrode under cap as needed 38 © 2014 Nuraleve, Inc. Proprietary and Confidential.

39. Tips and Tricks W HAT YOU DON ’ T WANT : Dripping electrodes If liquid leaks around the contact area, it may:  Short the contact between electrodes (ineffective session)  Change the area of contact between electrodes (modifies effectiveness) Too much or too little liquid affects the current density Prevention:  Squeeze out excess saline before patient application 39 © 2014 Nuraleve, Inc. Proprietary and Confidential.

40. Questions? 40 © 2014 Nuraleve, Inc. Proprietary and Confidential. 1.888.792.7922 Ext. 103 crystal@nuraleve.com