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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

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
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

attempted neuromodulation via ultrasound
‘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
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

hardware single fus transducer
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

hardware software
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)
changes in extracellular neurotransmitters
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.
modulation of ec neurotransmitters
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

expedited recovery from the anesthesia
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
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

summary
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
acknowledgement
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)