1. 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

2. Fundamental 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?

3. 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)

4. l 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 l 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

5. 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...

6. 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

7. 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.

8. Kindling Acquisition During acquisition there is a progressive increase in duration and complexity of electrographic seizure activity.

9. 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 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

11. Gaito, 1980; Gaito et al., 1980 1 st to report LFSWS interfered with kindled seizures Convoluted experimental design Results difficult to interpret Work not accepted, largely ignored 1 st to report LFSWS interfered with kindled seizures Convoluted experimental design Results difficult to interpret Work not accepted, largely ignored

12. 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. 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.

13. 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. 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.

14. 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 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

15. * ** * =P<0.01, n=6 Goodman et al. 2005

16. 6 Stimulation – No LFS 12 Stimulations - LFS 30sec LFSWS Goodman et al. 2005

17. ** * *** Goodman et al. 2005

18. *** Goodman et al. 2005

20. Goodman, 2005

22. LFSWS raises afterdischarge threshold McIntyre et al. 2002

23. Postictal LFSWS is also effective

24. Stimulation may become more effective over time

27. Possible Mechanisms l Long Term Depression (LTD)? l Depotentiation? l Total charge? l Does 1Hz stimulation mimic the interictal spike which has been hypothesized to be inhibitory? l Long Term Depression (LTD)? l Depotentiation? l Total charge? l Does 1Hz stimulation mimic the interictal spike which has been hypothesized to be inhibitory?

28. Sine vs. Square Wave (pulsatile)

29. 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

30. 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…..

31. Collaborators Helen Hayes Hospital SUNY Downstate Russell Berger Nick Hasulak Sheeja Thomas Jane Schon IBR Sudarshan Phani Daniel Erdheim Jared Zucker Mathew Pathrose NeuroPace Inc. Wadsworth Labs Thomas Tcheng, Ph.D Karen Smith Erem Boto William Shain, Ph.D. Helen Hayes Hospital SUNY Downstate Russell Berger Nick Hasulak Sheeja Thomas Jane Schon IBR Sudarshan Phani Daniel Erdheim Jared Zucker Mathew Pathrose NeuroPace Inc. Wadsworth Labs Thomas Tcheng, Ph.D Karen Smith Erem Boto William Shain, Ph.D.

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