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Focused Ultrasound: a New Evidence of Modulation of Neurotransmitters in CNS

Focused Ultrasound: a New Evidence of Modulation of Neurotransmitters in CNS. Seung-Schik Yoo, Ph.D., M.B.A. Tissue Imaging/Engineering Laboratory Dept. of Radiology, Brigham and Women’s Hospital, Harvard Medical School (USA). Non-invasive Direct Neuromodulation. 1. 2. 3.

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Focused Ultrasound: a New Evidence of Modulation of Neurotransmitters in CNS

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  1. Focused Ultrasound: a New Evidence of Modulation of Neurotransmitters in CNS Seung-Schik Yoo, Ph.D., M.B.A. Tissue Imaging/Engineering Laboratory Dept. of Radiology, Brigham and Women’s Hospital, Harvard Medical School (USA)

  2. Non-invasive Direct Neuromodulation 1 2 3 • Needed for the assessment of region-specific brain function • A new modality for functional brain mapping, including the evaluation of white matter connectivity. • Needed for the modification and control of brain function • Control of aberrant brain activities in neural circuitries • High-impact, potential therapeutic applications covering wide spectrum of neurological and psychiatric disorders. Limitations of current neuromodulation technique • ECT,DBS,EpCS: Invasive • tDCS, TMS: Lack spatial specificity and have limited depth penetration ECT tDCS DBS EpCS TMS Adapted from Hoy and Fitzgerald, Nature Review/Neurology, 2010

  3. ‘Attempted’ Neuromodulation via Ultrasound • Fry et al. (1958): Discovery of reversible neural suppression by focused ultrasound in cats • Gavrilov (1970’s-1980’s): Creation of neural sensation via FUS in humans • Magee (1993): Accidental discovery of auditory sensation during transcranial Doppler exam • Bachtold (1998): Reversible modulation of activity in ex vivo rodent brain tissue. But..… • Lacked systematic/modern approach • Lacked adequate hardware for the focused ultrasound • Use of mixed bands of frequencies, which are not optimized for the transcranial use. Gavrilov, et al. 1985

  4. Idea: Pulsed FUS • FUS can deliver acoustic energy to small and steerable regions of the brain (e.g HIFU for thermal ablative therapy of tumor). • Transcranial application < 1 MHz • Pressure waves are focused to small spot • Use only mechanical energy • Heat is not desired for safety reasons. • Pulsating acoustic pressure can alter the excitability in neurons. • Proposed method: Instead of continuous application of HIFU, apply the low intensityFUS stimulation as a train of pulses with sufficient inter-pulse intervals. Ultrasound transducer Acoustic Focus

  5. Hardware: Single FUS Transducer • Human applicator with image-guided tracking • Dual-channel, collimated ultrasound applicator for animal IR Marker Transducer Transducer Laser guide Motion camera

  6. Hardware/Software • Software • MRI-CT guided 3D Visualization • Ability to track head motion • Automatic data logging and archive • Integrated sonication control panel • Hardware • SonomoTM: Commercially-available • FUS unit + image-guidance unit • Base on a commercial IR optical tracking device (NDI, Canada)

  7. Changes in Extracellular Neurotransmitters • Suppressive sonication (TBD=0.5msec, PRF=100Hz, Ispta=130mW/cm2) was delivered to the thalamus. • Microdialysis was performed to sample GABA, glutamate, dopamine, and serotonin from the frontal lobe. • Samples were collected every 20 minutes through the circulation of artificial CSF.

  8. Modulation of Ec Neurotransmitters • No change in Ec Glutamate • Decreased Ec GABA: Increased up-take of GABA ? • Increased Ec Dopamine: Potential facilitation of DA release? • Increased Ec Serotonin: Potential inhibition of 5HT re-uptake? Glutamate GABA Dopamine 5HT

  9. Expedited Recovery from the Anesthesia • Excitatory FUS was given to the thalamus of the rats • Shortened the ketamine/xylazine anesthesia time • DBS to the intrathalamic nuclei (human) improved the awareness of the minimally-conscious state (MCS) patients • Potential application toward the consciousness

  10. Potential Mechanism? • Not temperature-related • e.g. MR thermometry shows no temperature change. • Not electro-magnetic (Eddy currents related) • e.g. observed regardless of the MR environment • Most likely, mechanical • FUS induces microscopic vibration • Mediates mechanoreceptor • Induces Ion channel operation Ultrasound Sonication Further neuro-modulation via plasticity And more… Changes in Excitability & Neuro-transmission Neuronal membrane

  11. Summary 1 2 3 4 Focused ultrasound can provide a new means for non-invasive, localized functional neuro-modulation. Bi-modal modes of modulation, i.e. excitation and suppression, are possible. FUS also changes the level of neurotransmitters, with potential implication in the treatment of psychiatric disorders. Future works • Assessment of different FUS frequency and parameters • Larger animal testing including the primates • Assessment of session-specific/accumulative effects • Assessment of neuromodulatory role in PNS, which may have impact on pain management

  12. Acknowledgement • Gerald J and Dorothy R Friedman Foundation • Focused Ultrasound Foundation • NARSAD • Center for Integration of Medicine and Innovative Technology • Incheon Saint Mary’s Research Grant • NIH National Center for Research Resources & NIH grant K24 RR018875 (to A. Pascual-Leone) • Byoung-kyong Min, Ph.D., Yongzhi Zhang, M.D., Krisztina Fischer, M.D., Ph.D., Nathan McDannold, Ph.D. (BWH), Kwang-ik Jung (Hallyn Univ) • Alvaro Pascual-Leone (BIDMC), Felipe Fregni (SRH) • Yongan Chung, M.D., Iso Maeng, M.D. (Incheon Saint Mary) • Emmanuel Filandrianos and Javig Taghahos (Boston Univ)

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