Transcript Brain Stimulation as a Therapy for Epilepsy

Low Frequency Sine Wave
Stimulation as
a Therapy for Epilepsy
Jeffrey H. Goodman, Ph.D
NYS Institute For Basic Research
In Developmental Disabilities
June 6, 2009
Fundamental Questions
• What type of stimulation should be used?
• Where to stimulate?
• Is the stimulus safe?
• Will the stimulation interfere with normal
brain function?
Why Low Frequency Stimulation?
“…low frequency stimulation possesses the greatest
potential for clinical benefit since the effect of the
stimulation can last well beyond the duration of
the pulse…; while high frequency stimulation
would increase synaptic efficacy, which could be
epileptogenic.”
Durand and Bikson (2001)
In Vitro Hippocampal Slice

Albensi et al., 2004
100Hz stim stopped interictal-like spikes
-spikes returned when stim ended
1Hz stim stopped interictal-like spikes
-spikes did not return when stim
ended
In Vitro slice continued...
• Barbarosie and Avoli (1997)
LFS (0.25-1.5Hz) blocked interictal and
ictal activity in the entorhinal
cortex
• Kano et al., 2002 (amygdala/perirhinal)
LFS (0.5-1Hz) blocked ictal activity in
perirhinal cortex
Clinical Evidence
• Low frequency stimulation of the cortex
• 0.9 Hz, 0.3msec pulse, square wave
• Decreased interictal and ictal activity in
patients
Yamamoto et al., 2006
Why Kindling?
• Repeated spaced presentations of an initially
subconvulsive stimulus results in permanent
change in brain function culminating in a
generalized motor seizure.
• Definable convulsive stages.
• Able to measure the duration of the
electrographic seizure.
• Investigator controls when a seizure will occur.
Kindling Acquisition
During acquisition there is a progressive increase in duration
and complexity of electrographic seizure activity.
Electrographic seizures are accompanied
by progressive behavioral changes
• There are 5 distinct behavioral stages
• Stages 1-2 equivalent to partial seizures
• Stages 3-5 generalized
• After 3 consecutive Stage 5 seizures the animal
is considered Fully Kindled
Gaito, 1980; Gaito et al., 1980
• 1st to report LFSWS interfered with kindled
seizures
• Convoluted experimental design
• Results difficult to interpret
• Work not accepted, largely ignored
Velisek et al., 2002
• Examined effect of LFS (1Hz - square) on
kindling acquisition
• Used immature animals
• LFS increased the number of stimulations
required for the animals to become fully
kindled.
Methods
•
Adult male Sprague-Dawley rats.
•
Bipolar electrodes were implanted bilaterally in the
basolateral amygdala or dorsal hippocampus.
•
Effect of preemptive LFSWS examined during
kindling acquisition and in fully kindled rats.
•
Effect of postictal LFSWS and LFPS was examined
in rats fully kindled in the amygdala.
Stimulation parameters
Kindling stimulus – 1-2sec, 400uA, 60Hz, 1msec pulse
LFSWS – 30sec, 50uA, 1Hz sine
LFPS – 15min, 50uA, 1msec pulse, pulsatile
Control Animals – Kindling stimulus only
Eperimental Animals – LFSWS + Kindling stim or LFPS + Kindling
stim
Effect of Low Frequency Stimulation on
AD duration
Control
Experimental
50
(mean±SEM)
AD Duration -sec
60
40
* * *
30
* * *
20
* =P<0.01, n=6
10
0
0
5
10
Stimulus Number
15
20
Goodman et al. 2005
6 Stimulation – No LFS
30sec
LFSWS
12 Stimulations - LFS
Goodman et al. 2005
Mean Behavioral Seizure Score
(mean±SEM)
Seizure Score
5
4
***
3
*
2
**
1
0
0
5
10
Stimulus Number
Control
15
Experimental
20
Goodman et al. 2005
AD Incidence During Acquisition
90
(mean±SEM)
AD Incidence -%
100
******
80
70
60
50
40
Control
Experimental
Goodman et al. 2005
LFS Induced Decrease of Seizures in Fully Kindled
Amygdala Rats
90
(mean±SEM)
Incidence of Stg 5
Seizures -%
100
80
70
60
***
***
50
40
30
Pre-LFS
Post-LFS
Goodman et al. 2005
100
90
(mean±SEM)
Incidence of Stg 5 Seizures-%
LFS Induced Decrease in Seizures in Fully
Kindled Hippocampal Animals
80
70
***
60
50
40
Pre-LFS
Post-LFS
Goodman, 2005
Incidence -% (mean±SEM)
Effect of LFS Square on Hippocampal Kindled
Seizures
100
90
80
70
60
50
40
Pre-LFS
Post-LFS
Goodman, 2005
LFSWS raises afterdischarge threshold
McIntyre et al. 2002
Postictal LFSWS is also effective
Stimulation may become more effective
over time
Possible Mechanisms

Long Term Depression (LTD)?

Depotentiation?

Total charge?

Does 1Hz stimulation mimic the interictal spike which
has been hypothesized to be inhibitory?
Sine vs. Square Wave (pulsatile)
Conclusions
• Preemptive LFSWS significantly decreased the
incidence of AD during kindling acquisition in
amygdala kindled rats.
• Preemptive LFSWS significantly decreased the
incidence of Stage 5 seizures in rats fully kindled in
the amygdala and hippocampus.
• LFSWS was also effective when delivered postictally
in amygdala kindled rats.
Conclusions continued…..
• Preemptive and postictal LFPS did not interfere with
kindled seizures.
• These results suggest that LFSWS may be an effective
therapy for the prevention of clinical seizures.
Collaborators
Helen Hayes Hospital
Russell Berger
Sheeja Thomas
Jane Schon
Sudarshan Phani
Jared Zucker
Mathew Pathrose
SUNY Downstate
Nick Hasulak
NeuroPace Inc.
Thomas Tcheng, Ph.D
Erem Boto
Wadsworth Labs
Karen Smith
William Shain, Ph.D.
IBR
Daniel Erdheim
Ultimate Goal
Design an implantable neurostimulator that combines
seizure detection with stimulation therapy