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Targeting and Safety Monitoring for LIFUP in First Human Trials

Targeting and Safety Monitoring for LIFUP in First Human Trials. Alexander Korb, PhD Mentor: Alexander Bystritsky, M.D., Ph.D. Objective. Develop a non-invasive neuromodulation system that can safely and accurately target the hypothalamus. ) ) ) ) ). Transducer. Outline. Background

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Targeting and Safety Monitoring for LIFUP in First Human Trials

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  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 ) ) ) ) ) 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 X Ultrasound

  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 9cm 20s 40s 60s 80s 100s 120s 140s 160s Δ0.36°C Δ0°C FUS ON 9cm FUS OFF

  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/cm2 Ispta

  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

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