Focused Ultrasound a New Evidence of Modulation of

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) 3/19/2018

Non-invasive Direct Neuromodulation • 1 Needed for the assessment of region-specific brain function – A new modality for functional brain mapping, including the evaluation of white matter connectivity. • 2 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. 3 Limitations of current neuromodulation technique – ECT, DBS, Ep. CS: Invasive – t. DCS, TMS: Lack spatial specificity and have limited depth penetration ECT t. DCS DBS Ep. CS TMS Adapted from Hoy and Fitzgerald, Nature Review/Neurology, 2010

‘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

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 Ultrasound transducer • Use only mechanical energy – Heat is not desired for safety reasons. – Pulsating acoustic pressure can alter the excitability Acoustic Focus in neurons. • Proposed method: Instead of continuous application of HIFU, apply the low intensity FUS stimulation as a train of pulses with sufficient inter-pulse intervals.

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

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

Changes in Extracellular Neurotransmitters • Suppressive sonication (TBD=0. 5 msec, PRF=100 Hz, Ispta=130 m. W/cm 2) 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.

Modulation of Ec Neurotransmitters Glutamate Dopamine • • GABA 5 HT 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 5 HT re-uptake?

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

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 Further neuro-modulation Changes in via plasticity Excitability & And more… Neuro-transmission Ultrasound Sonication Neuronal membrane

Summary 1 2 3 4 Focused ultrasound can provide a new means for noninvasive, 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

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 K 24 RR 018875 (to A. Pascual-Leone) • Byoung-kyong Min, Ph. D. , Yongzhi Zhang, M. D. , Krisztina Fischer, M. D. , Ph. D. , Nathan Mc. Dannold, 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)