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)
Thank you very much for the introduction. Good to be here this afternoon.
Other than pharmacological intervention, there have been only limited options available for doctors and scientists who wish to modify brain function in non-invasive manner.
So far, modification of brain function has been mostly based on the pharmacological intervention.
In this talk, I would like to present to you a completely new, non-invasive, non-pharmacological functional neuromodulation technique.
4/21/2017

2. Non-invasive Direct Neuromodulation1
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 2 3
Why do we need such a technique? First, it is needed for assessment of region-specific brain function. It can be used as ..
Secondly, it is needed for modification and control of brain function. It can be used as a modality which enables the control aberrant brain activity in neural circuitries.
Therefore, it will provide high-impact…
There are several non-pharmacological neuromodulation techniques available.
Adapted from Hoy and Fitzgerald, Nature Review/Neurology, 2010
ECT
tDCS
DBS
EpCS
TMS

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
We believe the ultrasound will play important roles in overcoming such limitations.
There have been several attempts to achieve neuro-modulation using ultrasound.
Pioneering work by Dr. William Fry reported the discovery…

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 intensity FUS stimulation as a train of pulses with sufficient inter-pulse intervals.
Ultrasound transducer
Acoustic Focus
- We found that pulsed application of focused ultrasound may play an important role in neuromodulation.

5. Hardware: Single FUS Transducer
Dual-channel, collimated ultrasound applicator for animal
Human applicator with image-guided tracking
IR Marker
Laser guide
Transducer
Transducer
Motion camera
Fortunately, there are commercially available systems out there.
An example of such system is shown here.
This is an example of single transducer FUS unit.

6. Hardware/Software Hardware Software SonomoTM: Commercially-available
FUS unit + image-guidance unit
Base on a commercial IR optical tracking device (NDI, Canada)
Software
MRI-CT guided 3D Visualization
Ability to track head motion
Automatic data logging and archive
Integrated sonication control panel
Hardware is available typically under 100K$, and include sonication unit and image-guidance unit to plan the sonication trajectory and its target treatment area.
Commercial infrared tracking device is used to visualize the anatomical structures.
Software allows the 3D visualization of treatment pathway, with ability to track the head motion. and has user-friendly features such as automatic data logging and archive.
The software also has user-friendly features as automatic data logging and archive. It also has integrated control panel show here in this figure

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.
We were further motivated to see whether the FUS can alter the extracellular levels of neurotransmitter.

8. Modulation of Ec Neurotransmitters
Glutamate
GABA
Dopamine
5HT
We found that glutamate level was unchanged. GABA was reduced while both extracellular level of Dopamine and Serotonin increased.
Although detailed mechanism of these phenomena is unknown, the data shows promising potential that FUS can be applied to treat psychiatric and neurological diseases that are associated with aberrant neuro-transmission.
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?

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
We found that glutamate level was unchanged. GABA was reduced while both extracellular level of Dopamine and Serotonin increased.
Although detailed mechanism of these phenomena is unknown, the data shows promising potential that FUS can be applied to treat psychiatric and neurological diseases that are associated with aberrant neuro-transmission.

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
So.. What are the potential mechanism behind all these. Of course, detailed investigation is necessary to debunk all the questions.
However we know that this is not temperature related. It is NOT electromechanical effect either.
Therefore, it is reasonable to believe that is most likelt, still mechanical.
Changes in
Excitability &
Neuro-transmission
Further neuro-modulation
via plasticity
And more…
Neuronal membrane

11. Summary 1
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 2 3 4

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 RR (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)
I would like to gratefully acknowledge the financial support and our collaborators.
Thank you for your attention.