1. Targeting and Safety Monitoring for LIFUP in First Human Trials Alexander Korb, PhD Mentor: Alexander Bystritsky, M.D., Ph.D

2. Objective Develop a non-invasive neuromodulation system that can safely and accurately target the hypothalamus ) ) ) ) ) Transducer

3. Outline Background Technology Experiments Next Steps

4. Background Hypothalamus Target for insulin Center for appetite and satiety Deep Brain Stimulation (DBS) of lateral hypothalamus Weight loss in rats Indirect results in humans show potential Obici et al, 2002; Bernardis and Bellinger, 1996; Halpern et al, 2008; Sani et al, 2007; Torres et al 2011

5. DBS = X

6. Alternative to DBS Low-Intensity Ultrasound Pulsations (LIFUP) Highly focused Non-invasive Safe ) ) ) ) )

7. Outline Background Technology Experiments Next Steps

8. Ultrasound Traditional US Imaging Reflect acoustic energy Focused US Absorb acoustic energy Increased intensity to a small region Transducer ) ) ) ) ) ) ) ) ) ) ) ) ) ) )

9. LIFUP Neuromodulation Hippocampal excitation Motor activation Suppression of visual response Suppression of seizure activity Tyler et al, 2008; Tufail et al 2010; Min et al, 2011; Yoo et al, 2011

10. Challenges for Human LIFUP Skull absorbs energy Skull changes shape of beam focus Skull changes location of beam focus Invisible beam Ultrasound X

11. Goals of Experiments Assess feasibility Develop targeting Test safety

12. Outline Background Technology Experiments Next Steps

13. Feasibility in Large Mammalian Brain Anesthetized mini-pig Prepared skull Targeted hypothalamus with stereotactic frame ) ) ) Mulgaonkar et al 2012

14. Hypothalamic Stimulation P

15. Targeting with Thermometry Continuous US to cause heating Proton resonant frequency is proportional to temperature Δ0.36°C Δ0°C FUS ON FUS OFF 20s 40s 60s 80s 100s 120s 140s 160s 9cm

16. Skull Heating During LIFUP Near FDA limit for diagnostic US Only mild heating even after 5 minutes

17. Skull Heating During CW US 60s of continuous US 13.4W/cm 2 I spta

18. Goals of Experiments Assess feasibility Develop targeting Test safety ✓✓✓✓✓✓

19. Conclusions LIFUP can accomplish neuromodulation in deep brain structures MR-Thermometry can be used for targeting LIFUP is ready for human testing

20. Outline Background Technology Experiments Next Steps

21. First Human Experiments 10 patients with temporal lobe epilepsy Concurrent LIFUP and fMRI Outcomes: Absence of histological damage Neuromodulation Changes in epileptic activity Changes in seizure frequency

22. Thank You Thanks to the Friedman Diabetes Institute for their generous support of this project