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FUS-mediated reversible modulation of region-specific brain function in animal model

FUS-mediated reversible modulation of region-specific brain function in animal model. Jong-Hwan Lee*, Yongzhi Zhang*, Wonhye Lee*, Krisztina Fischer*, Alexander Bystritsky*, Nathan McDannold*, and Ferenc A. Jolesz*, and Seung-Schik Yoo*,.

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FUS-mediated reversible modulation of region-specific brain function in animal model

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  1. FUS-mediated reversible modulation of region-specific brain function in animal model Jong-Hwan Lee*, Yongzhi Zhang*, Wonhye Lee*, Krisztina Fischer*, Alexander Bystritsky*, Nathan McDannold*, and Ferenc A. Jolesz*, and Seung-Schik Yoo*, *Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School Presented to Gerald J. & Dorothy R. Freidman Foundation Symposium 2008

  2. www.biomag.hus.fi/tms/Thesis/dt.html Reversible and non-invasiveregional modulation of cortical function • Needed for short-term/long-term modulation of the brain function. • Ultimately, it may provide non-pharmaceutical intervention of appetite control ! • Transcranial magnetic stimulation (TMS) suffers from limited penetration depth and lacks spatial specificity. • Transcranial direct current stimulation (tDCS) lacks spatial specificity. • Deep brain stimulation (DBS) is invasive.

  3. Idea: Pulsed FUS (FUP) • Motivation and Earlier work • Trans-skull delivery of FUS (Hynynen et al. 2004) • Reversible modulation of activity in ex vivo brain tissue (Bachtold et al. 1998) • Previous works on animal sciatic nerves. • Things to avoid; • Irreversible tissue damage or seizure induction. • BBB disruption. • Excessive heating. • Proposed method: Instead of continuous application of HIFU, apply the low intensity FUS stimulation with sufficient inter-stimulation intervals as a train of pulses.

  4. TRIAL EXAMPLE FUP application and intensity adjustment A Recovery 45s 50 W/cm2 12 s 15 s 15s T-1 signal equl 12 s 21 s 21 s stimulation stimulation T-1 signal equl No stimulation No stimulation Initial excursion: Real-time fMRI during FUP • Why real-time fMRI? • To monitor the blood-oxygenated-level-dependent (BOLD) MRI signals that are associated with the activation in real-time, non-invasively. • Allows the adjustment of the FUP parameters on-fly. Detected activation at p<0.001 level and approximate location of the FUP application in yellow circle.

  5. MRI Room Control Computer Rabbit Sonication target Function Generator Plastic plate Brain MRI Coil Amplifier Water bag Skull Power Meter Water tank Ultrasound beam Matching Network Positioning system Transducer Experimental flow • Spotting of the FU ‘hot spot’ using phantom • 690 KHz ultrasound transducer with 8 cm focal depth • Anatomical localization • Functional localization via fMRI • BOLD-sensitive EPI sequence to detect level of activation • Adjustment of positioning system • Application of FUP with fMRI • fMRI without FUP to monitor • MRI Thermometry • Fast SPGR sequence; phase Dependent thermometry • [Group#1] Perfusion of Trypan blue to examine BBB disruption, followed by the histological analysis. • [Group #2] Survival for 1 week with behavior observation, followed by the histological analysis

  6. Experimental setup 3T MRI rtfMRI Processor MRI Console Pulse Regulator Pulse Monitor Power Monitor Function Generator Power Amplifier

  7. FUP application 9 s 45 s 12 s 15 s stimulation No stimulation Event-related response and FUP • In order to capture the effect of FUP during short-trial based visual stimulation, event-related fMRI design was adapted. • FUP (500 μs duration and 10 msec inter-pulse-interval) at 50W/cm2 intensity was applied for 9, 18, and 27 sec. Temporal progression of activation • L • R • C PreFUP • FUP BOLD Contrast (%) measured from each session • 3min • 5min • 7min • 11min

  8. B A C D E McDannold et al. BWH, PNAS 2007 Presence of BBB disruption or tissue damage? • Trypan Blue perfusion after FUP (within 30min) showed no apparent BBB disruption. • Histological analysis (H&E stain) showed no tissue damage even at 350W/cm2 pulse (10 msec inter-pulse-interval) application of the FUP for 27 sec. • Survival experiment showed normal post-FUP animal behavior and normal histology results.

  9. 27s 18s 9s MR Thermometry • No temperature rise during 27s application of FUP at 500 μs duration and 10 msec inter-pulse-interval at 50W/cm2 intensity. – Virtually no temperature change • Even at higher level of energy at 350W/cm2 intensity, only 0.95 C rise of temperature was detected after 27s FUP application.

  10. Conclusions Reversible modulation of region-specific brain function was demonstrated via pulsed application of focused ultrasound energy. The given FUP parameter appears to be safe to be used, both short-term and long-term. The BOLD signal showed that the visual-stimulation-induced activation was enhanced during the FUP application, followed by the period of non-responsive stages, which suggest the ‘relative refractory period’.– More confirmatory study is needed using different stimulation parameters. Potential mechanism ? Temperature-mediation was ruled out. Possibly via mechanical modulation. Electrophysiological confirmation will be followed.

  11. Future Direction Application of the FUP to modulate neural circuitries in hypothalamus (targeting ventromedial nucleus), and subsequent appetite control. Testing on obese ob/ob Leptin deficient mice Effect of down-regulation ? Effect of up-regulation ? Challenges Size of region-of-interest in mouse is small. Potential induction of modulation in other neuro-endocrine systems. From Harlan catalogue

  12. Acknowledgement Magdalini C. Pilatou, Ph.D. Lisa Treat, M.S. Jason White, Ph.D. and with the financial support from Gerald J. & Dorothy R. Freidman Foundation Focused Ultrasound Surgery Foundation Bystritsky Family Foundation , and all anonymous rabbits… Disclaimer: This rabbit was NOT used in the experiment

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