Targeting and Safety Monitoring for LIFUP in First Human Trials

Alexander Korb, PhDMentor: Alexander Bystritsky, M.D., Ph.D

Objective

Develop a non-invasive neuromodulation system that can safely and accurately target the hypothalamus

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OutlineBackground

Technology

Experiments

Next Steps

BackgroundHypothalamus

Target for insulin Center for appetite and satiety

Deep Brain Stimulation (DBS) of lateral hypothalamus Weight loss in rats Indirect results in humans show potential

Obici et al, 2002; Bernardis and Bellinger, 1996; Halpern et al, 2008; Sani et al, 2007; Torres et al 2011

DBS = X

Alternative to DBSLow-Intensity Ultrasound Pulsations

(LIFUP)Highly focusedNon-invasiveSafe

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OutlineBackground

Technology

Experiments

Next Steps

UltrasoundTraditional US Imaging

Reflect acoustic energy

Focused USAbsorb acoustic energy Increased intensity to a

small region

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LIFUP NeuromodulationHippocampal excitation

Motor activation

Suppression of visual response

Suppression of seizure activity

Tyler et al, 2008; Tufail et al 2010; Min et al, 2011; Yoo et al, 2011

Challenges for Human LIFUPSkull absorbs energy

Skull changes shape of beam focus

Skull changes location of beam focus

Invisible beam

UltrasoundX

Goals of ExperimentsAssess feasibility

Develop targeting

Test safety

OutlineBackground

Technology

Experiments

Next Steps

Feasibility in Large Mammalian Brain

Anesthetized mini-pig

Prepared skull

Targeted hypothalamus with stereotactic frame

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Mulgaonkar et al 2012

Hypothalamic Stimulation

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Targeting with Thermometry

Continuous US to cause heating

Proton resonant frequency is proportional to temperature Δ0.36°C

Δ0°C

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9cm

9cm

Skull Heating During LIFUPNear FDA limit for

diagnostic US

Only mild heating even after 5 minutes

Skull Heating During CW US

60s of continuous US

13.4W/cm2 Ispta

Goals of ExperimentsAssess feasibility

Develop targeting

Test safety

✓

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ConclusionsLIFUP can accomplish neuromodulation in deep

brain structures

MR-Thermometry can be used for targeting

LIFUP is ready for human testing

OutlineBackground

Technology

Experiments

Next Steps

First Human Experiments10 patients with temporal lobe epilepsy

Concurrent LIFUP and fMRI

Outcomes:Absence of histological damageNeuromodulationChanges in epileptic activityChanges in seizure frequency

Thank YouThanks to the Friedman Diabetes Institute for their generous support of this project