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

04/22/23

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• 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

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Adapted from Hoy and Fitzgerald, Nature Review/Neurology, 2010

ECT tDCS DBS EpCS TMS

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‘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

• 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

Hardware: Single FUS Transducer • Dual-channel, collimated

ultrasound applicator for animal• Human applicator with

image-guided tracking

IR Marker

TransducerLaser guide

Motion camera

Transducer

Hardware/Software • Hardware 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

• 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.

Changes in Extracellular 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?

Modulation of Ec Neurotransmitters

Glutamate GABA

Dopamine 5HT

• 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

Expedited Recovery from the Anesthesia

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

Neuronal membrane

Changes inExcitability &

Neuro-transmission

Further neuro-modulation via plasticityAnd more…

SummaryFocused 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

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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)