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

6 Stimulation – No LFS

12 Stimulations - LFS30sec LFSWS

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

Goodman, 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

LFSWS raises afterdischarge thresholdLFSWS raises afterdischarge threshold

McIntyre et al. 2002

Postictal LFSWS is also effectivePostictal LFSWS is also effective

Stimulation may become more effective over timeStimulation may become more effective over time

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?

Sine vs. Square Wave (pulsatile)Sine vs. Square Wave (pulsatile)

• 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.

Ultimate Goal Design an implantable neurostimulator that combines seizure detection with stimulation therapy