1. Focused Ultrasound Neuromodulation of the Hypothalamus Alexander Korb, Ph.D. Mentor: Alexander Bystritsky, M.D., Ph.D

2. Background Hypothalamus is important in obesity and diabetes Target for insulin Center for appetite and satiety Deep brain stimulation (DBS) of hypothalamus Stimulation of lateral hypothalamus led to weight loss in rats Indirect observations of DBS in humans show potential for hypothalamic stimulation to lead to weight loss Obici et al, 2002; Bernardis and Bellinger, 1996; Halpern et al, 2008; Sani et al, 2007; Torres et al 2011

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

4. Neuromodulation Deep Brain Stimulation (DBS) Successfully targeted hypothalamus to reduce obesity Highly focused Requires invasive brain surgery Transcranial Magnetic Stimulation (TMS) Non-invasive Large focal area Low-intensity Focused Ultrasound Pulsations (LIFUP) Non-invasive Highly focused

5. LIFUP High-frequency pressure waves Focused mechanical energy Demonstrated neuromodulation in rats and rabbits Transducer ) ) Tyler et al, 2008; Tufail et al 2010; Min et al, 2011; Yoo et al, 2011

6. Modulating Hypothlamic Activity Anesthetized mini-pig Removed upper plate of skull Polished lower plate of skull Similar thickness to human temporal bone Focused US on hypothalamus using stereotactic frame ) ) )

7. Results

8. Challenges with Transcranial US Skull absorbs energy Skull changes shape of beam focus Skull changes location of beam focus Invisible beam Ultrasound X

9. For Use in Humans Accurately target deep brain structures Visualize beam focus Ensure patient safety Monitor temperature Transducer ) )

10. Targeting Magnetic resonance – acoustic radiation force imaging (MR-ARFI) Force of US displaces tissue Kaye et al, 2010

11. MR-ARFI Pulse Sequence Z Y X ADC RF Magnets Time Ultrasound

12. MR-Thermometry Proton spin is proportional to temperature Temperature changes visible as phase differences Standard fast spin echo pulse sequence

13. Conclusions LIFUP can accomplish neuromodulation in the hypothalamus MR-ARFI may be able to guide LIFUP to the appropriate target MR-Thermometry can be used to detect potentially harmful temperature changes LIFUP is almost ready for human testing.

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