1. Neurological Applications of Focused Ultrasound Nishanth Khanna MD, Victor Frenkel PhD, Andrew Steven MD, Dheeraj Gandhi MD, Elias Melhem MD Department of Radiology and Nuclear Medicine, University of Maryland School of Medicine ASNR 53 rd Annual Meeting Chicago, Il eEdE#: eEdE-81 (Shared Display)

2. Disclosures The authors declare no financial disclosures

3. Objectives Discussion of promising clinical applications Discussion of the physical principles of focused ultrasound (FUS) Familiarization with the FUS apparatus used in neurological applications Illustration of the variety of biological effects generated by varying FUS energy deposition

4. Focused Ultrasound A single element US transducer can focus acoustic wave propagation at a specific point The structure of the transducer depends on the target tissue The therapeutic benefit of FUS relies on energy deposition via acoustic wave propagation to a focal point

5. Focused Ultrasound Acoustic energy can be deposited in multiple layers of tissue in multiple dimensions within a targeted volume by steering the focal point

6. Focused Ultrasound (FUS) Applications Rate of Energy Deposition Neuromodulation Low Intensity Pulsed FUS Enhanced Drug Delivery High Intensity Pulsed FUS Thermal Ablation High Intensity Continuous FUS Destructive / Irreversible Biological Effects ‘Visible’ / Reversible ‘Invisible’ / Reversible

7. FUS for Thermal Ablation Lou et al 2007 J Ultrasound Med treated untreated Thermal ablation with FUS has high resolution with a sharp line of demarcation (approx. 8-10 cell diameters) between treated and untreated tissues FUS offers the added benefit of no radiation deposition when compared to other therapeutic systems (i.e. gamma knife)

8. Extra-neurological FUS applications Also approved for use in ablation of uterine fibroids via an MR-guided extracorporeal transducer Initially used in US-guided treatment of prostate cancer via a transrectal transducer

9. Noninvasive MR Thermometry Ranjan et al 2012 J Control Release Near real- time temperature measurement of FUS induced heat generation is possible via MR thermometry

10. Brain – The Focused Ultrasound Apparatus MRI offers guidance and monitoring of treatment The FUS apparatus A multi element, hemi- spherical, phased array FUS transducer

11. Brain – The Focused Ultrasound Apparatus Degassed water circulates in a “bladder” around the patient’s head for efficient acoustic wave propagation

12. High resolution, high energy deposition with one focal point Multiple focal points - larger area of relative hyperthermia to enhance radiotherapy Individual US elements can be steered to correct aberrations (i.e. at soft tissue- bone interfaces) A multi-element, phased array transducer offers versatility

13. Konofagou 2012 TheranosticsClement 2012 J Acoust Soc Am Transcranial FUS Exposures energy loss/heating reflection/refraction phase alteration the variable thickness of the skull further exacerbates the problem Impedance mismatch at soft tissue/bone & bone/soft tissue interface results in:

14. Hynynen et al 2006 Euro J Radiol Transcranial FUS Exposures X-ray computed tomography (CT) images are used to predict and correct longitudinal wave distortion created by the skull by steering individual ultrasound elements

15. Clinical Applications of High Intensity FUS – Essential Tremor A clinical trial performed in 2011 and published in 2013, enrolled 15 patients with refractory essential tremor to evaluate the role of MR- guided focused ultrasound

16. Before Clinical Assessment of Tremor Suppression After (same day) Elias et al 2013 NEJM

17. Clinical Assessment of Tremor Suppression Elias et al 2013 NEJM All but one of the patients experienced significant improvement in symptoms lasting at least one year after therapy

18. Unilateral Thalamotomy of the Ventral Intermediate Nucleus – MRI Findings Clinical benefit persisted well after resolution of MRI findings without evidence of non-target intracranial injury Elias et al 2013 NEJM

19. Other Clinical Applications of High Intensity FUS

20. Early clinical trials suggest utility in thermal ablation of solid intracranial tumors Other Clinical Applications of High Intensity FUS Jolesz 2014 Annu Rev Med

21. continuous, high intensity heat coagulative necrosis uterine fibroids, solid tumors, thalamus I t FUS Duty Cycle and Mechanisms

22. continuous, high intensity heat coagulative necrosis uterine fibroids, solid tumors, thalamus pulsed, high intensity acoustic cavitation, acoustic rad force increased permeability enhanced drug/gene delivery I t I t FUS Duty Cycle and Mechanisms When applied in a pulsed, high intensity manner, cooling between the pulses and lower average temporal intensity result in lower temperature elevations. Mechanical effects of FUS will predominate

23. FUS with Ultrasound Contrast Agents Ultrasound Contrast Agents WithoutWith Varying pressure field of the FUS acoustic wave causes oscillation of the bubbles of US-contrast agents

24. Blood Brain Barrier Opening - Mechanisms Liu et al 2014 Theranostics Various interactions of the US-contrast bubbles with the endothelial wall creates transient increase in permeability

25. Enhanced Drug Delivery in the Treatment of Glioblastoma

26. Wei 2011 PloS One Visualization of BBB opening Post-gadolinium enhancement serves as a surrogate for visualization of BBB opening

27. Monitoring Tumor Growth A T2 sequence was used to monitor growth and decide the initiation of treatment (Day 10). After achievement of adequate tumor burden, treatment was initiated and tumor response was assessed (Day 17). The FUS + Temozolomide group demonstrated lower rate of tumor growth Wei 2011 PloS One

28. Tumor Growth and Survival Benefit Importantly, improved outcomes were also demonstrated in the FUS + treatment group Wei 2011 PloS One

29. Temozolomide Wei et al 2013 PloS One Doxil Treat et al 2011 Ultrasound Med Biol Herceptin Konoshita et al 2006 Proc Natl Acad Sci boronophenylalanine-fructose (BPA-f) Yang et al 2014 PloS One Ab - amyloid-β peptides Jordao et al 2013 Exp Neurol Glial cell line-derived neurotrophic factor (GDNF) Wang et al 2012 Plos One Stealth, brain-penetrating nanoparticles Nance et al 2014 J Control Release Neural Stem Cells Burgess et al 2011 Plos One NK-92 cells Alkins et al 2013 Cancer Res Other Examples of FUS Enhanced Delivery in Preclinical Trials

30. continuous, high intensity heat coagulative necrosis uterine fibroids, solid tumors, thalamus pulsed, high intensity acoustic cavitation, acoustic rad force increased permeability enhanced drug/gene delivery I t I t HIFU Duty Cycle and Mechanisms

31. continuous, high intensity heat coagulative necrosis uterine fibroids, solid tumors, thalamus pulsed, high intensity acoustic cavitation, acoustic rad force increased permeability enhanced drug/gene delivery pulsed, low intensity bilayer sonophores? acoustic rad force? mechanical perturbation neuromodulation: - stimulation - suppression I t I t I t HIFU Duty Cycle and Mechanisms Pulsed, low intensity application can generate neuromodulation; although, the exact mechanisms remain unclear.

32. FUS Induced Neuromodulation Reproducible in vivo neurostimulation of the mouse somatomotor response measured via EMG in the corresponding limb

33. FUS Induced Neuromodulation Selective in vivo neurostimulation of the mouse somatomotor cortex shows increased probability of muscle contraction and contraction strength at acoustic intensity ≥ 1.1 W/cm^2. Above this level, contraction duration and strength peaks and stabilizes, an “all or none” phenomenon

34. HIFU-induced in vivo neurostimulation and suppression of rabbit eloquent cortex

35. Reproducible, FUS-induced neurostimulation confirmed by functional MRI and electrophysiological recordings

36. FUS Suppression of VEPs Suppression of visual evoked potentials (VEPs) after focused ultrasound application confirms neuromodulation After experimentation, excision and histologic examination of the brain parenchyma demonstrated no evident injury

37. Potential Clinical Applications of Neuromodulation Functional evaluation when used in conjunction with functional imaging techniques Expanding on understanding of psychiatric illness and other neuropathologies Therapeutic tool in disorders that may benefit from neuroexcitation/suppression, i.e. epilepsy, obsessive compulsive disorder

38. Summary Neurological FUS has the potential to be a transformative technology in neuroscience and therapeutics Neurological applications include thermal ablation, enhanced drug delivery and neuromodulation in the context of noninvasive therapies or neuroconnectivity studies FUS is the only system that offers noninvasive, localized and transient permeability of the blood brain barrier Unique benefits of FUS over other therapeutic systems include noninvasiveness, lack of radiation and high tissue resolution

39. References Ranjan A, Jacobs G, Woods DL, et al. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. Journal of Controlled Release. 2012;158(3):487-494. Konofagou EE. Optimization of the Ultrasound-Induced Blood-Brain Barrier Opening. Theranostics. 2012;2(12):1223- 1237. Hynynen, K., McDannold, N., Clement, G., Jolesz, F. A., Zadicario, E., Killiany, R.,... & Rosen, D. (2006). Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain—a primate study.European journal of radiology, 59(2), 149-156. Elias, W. J., Huss, D., Voss, T., Loomba, J., Khaled, M., Zadicario, E.,... & Wintermark, M. (2013). A pilot study of focused ultrasound thalamotomy for essential tremor. New England Journal of Medicine, 369(7), 640-648. Jolesz, F. A. (2009). MRI-guided focused ultrasound surgery. Annual review of medicine, 60, 417. ExAblate Neuro: Focused Ultrasound Transcranial Neurosurgery. http://www.insightec.com/contentManagment/uploadedFiles/fileGallery/Brochure_ExAblateNeuro.pdf Accessed March 2, 2015 http://www.insightec.com/contentManagment/uploadedFiles/fileGallery/Brochure_ExAblateNeuro.pdf Foster RS, Bihrle R, Sanghvi N, et al. High-intensity focused ultrasound in the treatment of prostatic disease. European urology 1992;23:29-33 Tyler WJ, Tufail Y, Finsterwald M, et al. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PloS one 2008;3:e3511 Yoo SS, Bystritsky A, Lee JH, et al. Focused ultrasound modulates region-specific brain activity. NeuroImage 2011;56:1267-1275

40. Questions? nkhanna1@umm.edu