Focused ultrasound reduces epileptic EEG bursts

Department of Radiology

Brigham and Women's Hospital

Harvard Medical School

Byoung-Kyong Min

Introduction Method Result Discussion

Treatment on Neurological Disorders

• Representative non-invasive treatment on the brain: Medication

• However, it has side-effect and non-spatially specificity

•

Introduction Method Result Discussion

Non-pharmacological neuro-modulation

• Invasive tools (e.g. EpCS, DBS)

• Non-invasive tools (e.g. TMS, tDCS)

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

tDCS

DBS

TMS

EpCS

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

• Image-guided, non-invasive, spatially-accurate focused-ultrasound (FUS) could be a potent tool for neuro-modulation.

Introduction Method Result Discussion

Focused-Ultrasound Sonication (FUS)L1L2

IR Marker

TransducerLaser guide

Motion camera

Exablate (Insightec and GE): Array of small 1000 transducers

Introduction Method Result Discussion

Fig. TBD: tone-burst-duration, PRF: pulse repetition frequency, AI: acoustic intensity

Idea: Pulsed application of FUSTo avoid heating the tissue, pulsed sonication is used rather than continuous sonication.

• FUS suppresses VEP in LGN-sonicated cats (Fry, et al. 1958)• FUS affects the neurophysiology of in vitro local neural circuitry (Bachtold, et al. 1998, Rinaldi, et al. 1991)• FUS can temporarily modify the excitability of the neuronal tissue (Gavrilov et al. 1996)

Previous observations by FUS

Introduction Method Result Discussion

A

B

FUS transducer

B

Superior

Inferior

A

Caudal

Rostral

RightLeft

RightLeft

C

*

Minutes

B

Pre SonicationPost SonicationRecovery

A

Fig. Visual evoked potentials (A) and normalized amplitudes of the p30 components (B)

Fig. FUS-mediated fMRI activation maps of the motor cortex (A & B) and FUS-mediated BOLD signal time course (C: gray bar: sonication)

1. Excitation (Yoo et al., 2008; 2009)

2. Suppression (Yoo et al., 2008; 2009)

• We were motivated to examine if the FUS could suppress hyper-excitability of neural tissue based on a chemical kindling model of acute-stage epilepsy.

• Epilepsy is a chronic neurological disorder (~50 million), and is characterized by seizures (abnormal hyper-excitability of neurons).

• Since PTZ (pentylenetetrazol) was used to induce epileptic activity and progressive increments of theta activity has been reported during PTZ-induced epilepsy, not only raw EEG but also its theta band was assessed.

Introduction Method Result Discussion

Application to Epilepsy suppression

• Sprague–Dawley rats (275±30g)

• Group 1 (PTZ(+)/FUS(+); n=9), Group 2 (PTZ(+)/FUS(-) ; n=9), Group 3 (PTZ(-)/FUS(+) ; n=9)

• PTZ :GABAA receptor antagonist

45 mg/kg in 0.4 mL saline

Introduction Method Result Discussion

Fig. A diagram of the experimental apparatus

Experimental Setup & Design

Introduction Method Result Discussion

Transducer Characterization

TimeSpace

peak average

peak ISPTP ISATP

average ISPTA ISATA

• Mechanical Index (MI): the maximum peak negative pressure (Pr,α) of an ultrasound longitudinal wave divided by the square root of its center frequency (CMI)

• FUS transducer: 690 KHz, 7cm ROC, 6cm OD, 0.5 ms TBD, 100Hz PRF, 130 mW/cm2 (Ispta)=2.6 W/cm2 (Isppa)

Hydrophone

Fig. Transducer characterization

Transducer

• EEG measures: sub-dermal electrodes (5 mm lateral to the midline & 7 mm anterior to the lambda), 1KHz sampling rate

• Counting the number of raw EEG and theta bursts (4-8 Hz) exceeding the determined threshold (baseline σ × 4.75) in each session.

• Racine scoring & Histological analysis • Statistics: Independent t-test (one-tailed) between the two groups,

and paired t-test (one-tailed) within each animal. In order to compare body weights, a repeated-measures ANOVA with a covariance of the individual body weight before the experiment was applied.

Baseline(10 min)

Post1(10 min)

Pre-FUS(10 min)

PTZ Full ictalAnesthesia

FUS1(3min)

FUS2(3min)

Block-A Block-B Block-C Block-D Block-E Block-F

Post2(10 min)

Introduction Method Result Discussion

Fig. Flowchart of the EEG acquisition and FUS sonication

Raw EEG

EEG theta

100 μV

20 μV

10 sec

20 μV

1 min

100 μV

FUS2FUS1

10 sec

Introduction Method Result Discussion

Fig. The sample time-courses of EEG recordings from PTZ-induced epileptic rats with sonication.

A. Sample EEGs from Group 1 (PTZ(+)/FUS(+))

Raw EEG

EEG theta

100 μV

20 μV

10 sec

20 μV

1 min

100 μV

10 sec

Introduction Method Result Discussion

Fig. The sample time-courses of EEG recordings from PTZ-induced epileptic rats without sonication.

B. Sample EEGs from Group 2 (PTZ(+)/FUS(-))

• After sonication, the number of epileptic EEG bursts decreased.(‘Post1’: t(16)= -1.74; ‘FUS2’: t(16)= -2.03;‘Post2’: t(16)= -1.72).

• After 2nd sonication, the number of theta EEG bursts decreased. (‘Post2’: t(16)= -1.98)

A

B

Introduction Method Result Discussion

Group Analysis

Fig. Comparison of the average number of threshold-exceeding raw (upper) and theta (lower) EEG peaks between the FUS-treated and untreated groups.

• The number of epileptic EEG bursts within the FUS-treated group was significantly reduced after the sonication period

(‘Post1’: t(8)= 2.26; ‘FUS2’: t(8)= 1.91; ‘Post2’: t(8)= 2.58).

• The number of EEG theta peaks was significantly reduced during (63.0% reduction) and after (up to 68.5% reduction) the second sonication (‘FUS2’: t(8)= 2.81; ‘Post2’: t(8)= 3.14).

• Racine scores of the FUS-treated group during a day after the experiment were significantly lower than those of the control group (t(15)= -2.41; FUS-treated group: 0.33; Control group: 1.13).

Introduction Method Result Discussion

Summary

Introduction Method Result Discussion

Fig. Exemplary histological data obtained from Group 3 (left) H&E staining (right) TUNEL staining (DAPI in blue, apoptotic cell in green)

Histological Analysis

• The low-power, pulsed FUS sonication suppressed the number of epileptic EEG signal bursts without any significant tissue damages.

– Stretch-sensitive ion channels (e.g. the novel chloride channels) may be involved in modifying the excitability of neural tissue.

– Local hyperpolarization of the cell membrane would eventually raise the threshold for eliciting the epileptogenic activity.

– Synaptic contacts could be disrupted by ultrasound, reducing the propagation of the epileptic activity across the brain.

– Regulation of thalamic GABAergic inhibitory interneurons;

PTZ a GABAA receptor antagonist

• Therefore, FUS could provide a new non-invasive treatment of epileptic seizure.

Introduction Method Result Discussion

Discussion

• Intra-brain injection of KA (e.g. Hippocampus or amygdala) and evaluation of FUS on suppression of chronic focal epilepsy.

• Assessment of neurotransmitter modulation associated with sonication (Microdialysis).

• Stereotactic guidance:

MRI-compatible stereotactic positioning system

Acoustic radiation force impulse (ARFI) imaging

Introduction Method Result Discussion

Future Works

• Seung-Schik Yoo, Krisztina Fischer, Yongzhi Zhang, Ferenc A. Jolesz: Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

• Alexander Bystritsky: The Semel Institute for Neuroscience and Human Behavior, UCLA, LA, CA, USA

• Kwang-Ik Jung: Department of Physical Medicine & Rehabilitation, Hallym University Sacred Heart Hospital, Korea

• Lee-So Maeng, Sang In Park, Yong-An Chung: Institute of Catholic Integrative Medicine (ICIM), Incheon Saint Mary’s Hospital, Korea

Introduction Method Result Discussion

Acknowledgements