1. Neurostimulation: An Overview Thursday Feb 28 th Shaun Comfort, MD, MBA Adaptix Clinical Solutions, LLC American Society for Experimental NeuroTherapeutics | 15 th Annual Meeting

2. Disclosure(s) Consulting relationships with multiple Pharma, Bio, and Medical Device Companies Equity: J&J American Society for Experimental NeuroTherapeutics | 15th Annual Meeting Other: I will discuss some currently unapproved Rx/Research technologies Learning Objectives Outline the context & history of Neurostimulation Identify several current Neurostim therapies

3. The Brave New World of Neurostimulation American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

4. Basic Definitions Fundamental Quantity: Charge = Coulomb Negative Charges: Electrons = 1.6 x 10 -19 C Moving Charges: Current = Amp {C/sec} Charge Source (eg Battery): Voltage = Potential Energy/Ch = Volt {Joules/C} Useful Relation: Ohm’s Law V = iR Other Useful Terms: Frequency = Cycles/sec {Hertz} American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

5. Basic Definitions, cont American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

6. Neurostimulation? The modulation of nervous system activity by electrically activating individual or groups of neurons in the body, to achieve a clinical goal. Can be achieved using: Surface electrodes Implantable electrodes Indirect: Vector Force Fields (TMS) American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

7. Early Neurostimulation? First application of neurostimulation: Scribonius Largus, 65 AD Torpedo fish (electric ray) for relieving pain (Early TENS?) Empirical findings that electricity applied to skin had interesting effects such as pain reduction American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

8. Coincidental Physics American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

10. Faradization for Pain Relief American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

11. The Good Old Days? Early Faradization primitive and overly broad claims: “Electreat” device – Willie Kent 1 st person prosecuted under FD&C (1938) for Unsubstantiated Claims Claims later limited to pain However, this approach evolved into Transcutaneous Electrical Stimulation (TENS) used today for pain (eg, Shealy MD & Medtronics, 1970s) American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

12. Beyond Peripheral Faradization Early 20 th century - co-incident advances in electronics and medicine produced new tools for electrophysiology: ECG (1911), EEG (Berger, 1924) and therapy: ECT (Cerletti & Bini, 1938) American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

13. If That Is the Past, Where Are We Today? We are riding the 20 th Century wave of Neuroscience + Moore’s Law The results are: Implantable micro-electronics Open (VNS, DBS) - and Closed-loop (?) therapies Wireless monitoring (eg, Implanted EEG) Smart diagnostics (eg, ECG/EEG Interpretation) Rapid advances in Neurosurgery, fMRI, etc American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

14. Moore’s Law To 1 st approximation, doubling of transistor density & computing efficiency every 18 months American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

15. SCS, TENS, tDCS, etc American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

16. TENS, TMS, DBS, VNS, etc American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

17. NS Classification Grid ExternalImplanted Peripheral NS TENS - P n CI – Aud GES - GI SNS - GU Central NS ECT – Dep TMS – Dep TNS – HA tDCS SCS – Pn OI –Vis VNS-E p DBS-PD, E t, E p CtS - E p Aud = Auditory; CI = Cochlear Implant; CtS = Cortical Stimulation; Dep = Depression; E p = Epilepsy; E t = Essential Tremor; GI = Gastrointestinal; GNS = GastricElectric Stimulation; GU = Genitorurological; HA = Headache; OI = Occipital Implant;PD = Parkinson’s Dz; Pn = Pain/Analgesia; SCS = Spinal Cord Stimulation; SNS = Sacral Nerve Stimulation; TNS = Trigeminal Nerve Stmulation; Vis = Vision Current NS Treatment Modalities

18. What Are the Challenges? Clinical Trials: Demonstrating efficacy under placebo conditions difficult due to blinding & operator characteristics Long-term Stable Power Sources: Bigger batteries vs. recharging for implantables Closed Loop vs. Open Loop Methodologies Support: Implantable Neurostim looking much like pharma/biologic development: Time and $$$

19. Impact on Clinical Care and Practice NS has a long history of use in medicine NS is a useful adjunctive tool in the treatment of Neurologic conditions Several therapies have proven efficacy and safety for various disease conditions (eg, ET, Epilepsy) Much interest in new approaches: Implantable cortical and Deep Brain Stim for Epilepsy + other conditions Non-invasive surface Trigeminal & Vagal Stimulation Clinical trials, development timelines can be challenging NS is still maturing

20. Thank You! Contact Information: scomfort@adaptixcs.com

21. References/Data/Graphic Sources tp://en.wikipedia.org/wiki/Electric_current antenna-theory.com; Physlink.com, various Google Images tp://www.burtonreport.com/infspine/NSHistNeurostimPar tI.htm tp://www.burtonreport.com/infspine/NSHistNeurostimPar tI.htm thefullwiki.org; http://en.wikipedia.org/wiki/Electroconvulsive_therapy and../Electroencephalography http://www.economist.com/blogs/dailychart/2011/10/comp uting-power & letshavetheconversation.blogspot.com Osteoarthritis.about.com; Scientific American.com; http://www.burtonreport.com/infspine/NSHistNeurostimPar tI.htm Osteoarthritis.about.com; Medtronic.com; Cyberonics.com