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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
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 QuestionsFundamental Questions
• What type of stimulation should be used?• Where to stimulate?• Is the stimulus safe?• Will the stimulation interfere with normal
brain function?
• 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?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)
“…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)
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
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 Hippocampal Slice
• 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
• 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
In Vitro slice continued...
• 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
• 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
Clinical Evidence
Why Kindling?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.
• 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 AcquisitionKindling AcquisitionDuring acquisition there is a progressive increase in duration
and complexity of electrographic seizure activity.During acquisition there is a progressive increase in duration
and complexity of electrographic seizure activity.
Electrographic seizures are accompanied by progressive behavioral changesElectrographic 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
• 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., 1980Gaito, 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
• 1st to report LFSWS interfered with kindled seizures
• Convoluted experimental design• Results difficult to interpret• Work not accepted, largely ignored
Velisek et al., 2002Velisek 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.
• 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.
MethodsMethods
• 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.
• 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 parametersStimulation 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
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
* **
* =P<0.01, n=6
Effect of Low Frequency Stimulation on AD duration
0
10
20
30
40
50
60
0 5 10 15 20Stimulus Number
AD
Dur
atio
n -s
ec(m
ean±
SEM
)
Control
Experimental
* * *
Goodman et al. 2005
**
*
Mean Behavioral Seizure Score
0
1
2
3
4
5
0 5 10 15 20Stimulus Number
Seiz
ure
Scor
e(m
ean±
SEM
)
Control Experimental
***
Goodman et al. 2005
***
AD Incidence During Acquisition
40
50
60
70
80
90
100
Control Experimental
AD
Inc
iden
ce -%
(mea
n±SE
M) ***
Goodman et al. 2005
LFS Induced Decrease of Seizures in Fully Kindled Amygdala Rats
30
40
50
60
70
80
90
100
Pre-LFS Post-LFS
Inci
den
ce o
f S
tg 5
S
eizu
res
-%(m
ean
±S
EM
)
*** ***
Goodman et al. 2005
Effect of LFS Square on Hippocampal Kindled Seizures
40
50
60
70
80
90
100
Pre-LFS Post-LFS
Inci
denc
e -%
(mea
n±SE
M)
Goodman, 2005
Possible MechanismsPossible Mechanisms
Long Term Depression (LTD)?
Depotentiation?
Total charge?
Does 1Hz stimulation mimic the interictal spike which has been hypothesized to be inhibitory?
Long Term Depression (LTD)?
Depotentiation?
Total charge?
Does 1Hz stimulation mimic the interictal spike which has been hypothesized to be inhibitory?
• 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.
• 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
• 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.
• 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.
Conclusions continued…..
CollaboratorsCollaborators
Helen Hayes Hospital SUNY DownstateRussell Berger Nick HasulakSheeja ThomasJane Schon IBRSudarshan Phani Daniel ErdheimJared ZuckerMathew Pathrose
NeuroPace Inc. Wadsworth LabsThomas Tcheng, Ph.D Karen SmithErem Boto William Shain, Ph.D.
Helen Hayes Hospital SUNY DownstateRussell Berger Nick HasulakSheeja ThomasJane Schon IBRSudarshan Phani Daniel ErdheimJared ZuckerMathew Pathrose
NeuroPace Inc. Wadsworth LabsThomas Tcheng, Ph.D Karen SmithErem Boto William Shain, Ph.D.