focused ultrasound reduces epileptic eeg bursts department of radiology brigham and women's...
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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