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

1. Focused Ultrasound: a New Evidence of Modulation of Neurotransmitters in CNS 9/2/2012 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. 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.

2. 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 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.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.

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. 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� 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. - We found that pulsed application of focused ultrasound may play an important role in neuromodulation. - 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 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. 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 SonomoTM: Commercially-available FUS unit + image-guidance unit Base on a commercial IR optical tracking device (NDI, Canada) Hardware is available typically under 100K$, and include sonication unit and image-guidance unit to plan the sonication trajectory and its target treatment area. Commercial infrared tracking device is used to visualize the anatomical structures. Software allows the 3D visualization of treatment pathway, with ability to track the head motion. and has user-friendly features such as automatic data logging and archive. The software also has user-friendly features as automatic data logging and archive. It also has integrated control panel show here in this figureHardware is available typically under 100K$, 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. 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 We were further motivated to see whether the FUS can alter the extracellular levels of neurotransmitter.We were further motivated to see whether the FUS can alter the extracellular levels of neurotransmitter.

8. 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 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.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.

9. 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 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.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 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.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.

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