DEEP BRAIN STIMULATION FOR THE TREATMENT OF BRAIN SEIZURES

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1 1 DEEP BRAIN STIMULATION FOR THE TREATMENT OF BRAIN SEIZURES Juanjo Solano School of Electrical and Electronic Engineering University of Manchester, UK 26th March 2009 Abstract The fact that electrical stimulation of the deep brain reduces seizures activity is clearly demonstrated by means of several studies concentrated in thetreatment of brain diseases. This article shows how electrodes or other devices are implanted inside the head for supplying an excitation current in order to obtain important results about seizures reduction. Some different pulses are generated, so waveform recordings could be possible and neural responses to the various stimulation waveform could be compare. All this, has to be made taking into account the electrical stimulation parameters, due to the fact that energy injected into the brain is a tissue damage factor. For that reason, a Total Electrical Energy Delivered (TEED) equation is of great interest in our research. Index Terms Deep brain stimulation, Electrical stimulation, Thalamus, Epilepsy, Temporal lobe seizures I. INTRODUCTION Significant improvements with respect to the severity of the brain seizures has been obtained by means of electrical stimulation studies. This stimulation is being taken through the electrodes and programmable devices implantation inside the brain, mostly located in the thalamus nucleus, hippocampus or, in a more general region concerning both, the temporal lobe. A previous scalp video-eeg monitoring is, in most cases, necessary to charecterize seizure types and localization. After that, stimulation lead electrodes can be implanted. By means of an electrical current delivered on deep brain, whose stimulation parameters can be adjusted in terms of amplitude, pulse, time, frequency and voltage, seizures improvements were obtained. Deep brain responses are sensitive to the stimulation waveforms, and different neural responses are performed depending on which one is selected. Obtaining a deep brain stimulation equation and a equivalent electrical circuit is one objective to be reached beyond. II. METHODS As demonstrated in [1], electrical stimulation of the Anterior Nucleus of the Thalamus (ANT) reduces seizure activity. Human ANT stimulation was performed through bilateral implantable and programmable devices, as shown in Fig. 1 and Fig. 2. By means of Magnetic Resonance Imaging (MRI), placement location of the stimulation leads was confirmed. Stimulation was performed intermittently, with the stimulation system Fig. 1. Magnetic Resonance Imaging demonstrating localization of stimulation electrodes after implantation on each side set to deliver 1 min of stimulation every 10 min. Stimulation on one side was offset by 5 min from stimulation on the opposite side. A bipolar, alternating current was performed with the following stimulation parameters: 100 cycles/s (maximum amplitude of 10 Hz); pulse width set to 90 ms and voltage between 1.0 and 10 V. No current technical limits were found, at least within human deep brain stimulation. Experiments in rats [2], where its forebrain was removed and sliced, suggest some limits in frequency stimulation. A concentric bipolar stimulating electrode was placed in the STN (Subthalamic Nucleus), in order to deliver a electrical current with the following parameters: duration between 100 and 200 ms, amplitude from 10 to 500µ A and frequency Hz. We can find some other studies for treating epilepsy disorder by means of hippocampus stimulation, a brain region of main interest for us. In [3] it can be found a hippocampal electrical

2 2 Fig. 4. Position of depth and subdural electrodes. Magnetic Resonance Imaging (MRI) sections showing the position of bilateral depth electrodes placed within the hippocampal axis Fig. 2. Brain MRI demonstrating localization of stimulation electrodes in anterior nucleus of the thalamus Fig. 3. Hippocampal electrode implantation Fig. 5. Position of depth subdural electrodes. Axial MRI section showing the position of unilateral electrode placed on the pial surface of the right basotemporal cortex stimulation study where human hippocampus is stimulated at 90µ sec and 190 Hz, by means of 3 pairs of electrodes (each containing two 1-month treatment period) implanted inside human brain, view Fig. 3. In that case, electrical stimulation is being explored as a theraphy for leading in mesial temporal lobe epilepsy reduction. During each treatment pair, the stimulator was randomly turned ON 1 month and OFF 1 month, with the intention of compare outcomes between both periods. In other researches on hippocampus electrical stimulation, like [4],the definite position of both depth subdural electrodes is determined by MRI (Magnetic Resonance Imaging) studies, see Fig. 4 and Fig. 5. Wave pulses were applied with the following stimulation parameters: 130 Hz in frequency, 450µs in duration, µA in amplitude. Every 23 or 24 hours the stimuli was delivered for 2 3 weeks. This procedure was called SAHCS (Subacute electrical stimulation of the hippocampal formation), and is a safe method that can suppress temporal lobe epileptogenesis with no additional damage to the stimulated tissue. Charge or energy injected into the brain is known to be a co-factor in stimulation tissue damaged. It is also well known that the therapeutic benefit achieved by deep brain stimulation is primarily dependent on precise electrode placement and careful clinical selection of stimulation parameters (Moro et.al. 2000, Rezai et.al. 2006, Volkmann et.al 2006). In the study made by Christopher R. Butson and Cameron C. McIntyre [5],2 IPG (Implantable Pulse Generator) models were used to produce different stimulation waveforms with the aim to evaluate and compare them. Stimulation parameters were set in each IPG model, and waveforms were recorded at 1V; 60µsec, 120µsec, 210µsec and 450µsec pulse width; 100Hz, 130Hz and 185Hz. After that they were compared to different waveforms that adhered to the parameters parameters specified in the programming device. A computational model is used to predict the neural response to the various stimulation waveforms. Stimulation waveforms directly affect the neural response to deep brain stimulation, and they must be biphasic to prevent tissue damage [5]. Waveforms generated by the IPG consist of a cathodic pulse, a brief inter-pulse delay, and a charge-balancing anodic pulse. The cathodic (negative) phase of the waveform has the greatest effect on the neural activation.recordings were made at 50Hz with a 1000Ω load

3 3 Fig. 6. Position of the depth and subdural stimulation contacts. Diagram of the basotemporal cortex showing the position of the stimulation contact pairs in different patients. Arrows indicate the sites where subacute electrical stimulation of the hippocampal formation or gyrus (SAHCS) produced evident and fast antiepileptic responses. AHC = anterior hippocampus; MHC = medial hippocampus; PoHC = posterior hippocampus (Armon s horn); Am = amygdala; PS = presubiculum; PHC = parahippocampal gyrus; EC = entorhinal cortex; FUS = fusiform gyrus; IT = inferior temporal gyrus impedance connected between the IPG output and case during stimulation, view Fig. 7A. Comparison between waveforms recorded from the IPGs to a set of idealized waveforms generated was made using Matlab, see Fig. 7B. As mentioned above, brain tissue could be damaged by energy reception. In turn, the cathodic charge per phase for each waveform was calculated after connecting the voltage waveforms (both IPGs are voltage-controlled devices) to current waveforms using Ohm s law (taking into account the 1000Ω load which was meant to mimic the tissue impedance), and then integrating the area under the cathodic phase. In order to know and control how much charge is passed to the brain tissue, a equation that assess it is needed. Adam M. Koss et.al. [6], tried to develop a formula as exact as possible about the total electrical energy delivered by deep brain stimulation systems. Other studies suggest about magnetic brain stimulation. Xuemin. Wang et.al. [7], used a multi-channel magnetic system which can simultaneously stimulate different regions Fig. 7. Experimental and model configuration. A) Waveforms from Soletra and Kinetra IPGs were recorded in a monopolar configuration with a 1000Ω impedance between a single contact output and the IPG case. B) In addition, three waveforms were constructed in Matlab: Monophasic, Biphasic-Idealized abd Biphasic-Reduced. The duration of 11 anodic phase in the biphasic waveforms was determined from the Soletra duration (bottom) as shown in this example. The two biphasic waveforms differ primarily in the amplitude of the cathodic phase of the brain, expecting better results than by conventional stimulation. The stimulator was composed by 119 coils of 20mm in diameter and 20mm in length, placed in a spherical cap. In Fig. 8(a) the distribution of coils is shown and Fig. 8(b) is the real picture correspondingly. Each oil was connected to an independent driving circuit, so all the coils can be controlled independently. As seen in Fig. 9, a schematic diagram of the circuit, C2 is the charge and discharge capacitor. C1, D1 and D2 constitute the voltage doubling rectifying part, which supplies DC (Direct Current) to C2. For the control of the working state of C2, a switching device was used, called the silicon controlled rectifier (SCR),

4 4 Fig. 10. Placement of the coils ered as a solenoid, which can be thought as an integration of N turns of one-layer circle coils. The magnetic field B induced by the solenoid at the point r is given by: B = N µ 0 I d lx r 4 π r 3 (1) where I is the current in the coil, and N is the turns of the coil. The placement of the coils is show in Fig. 10. By means of a small director coil, and using a oscillograph to measure the inducted electromotive force of it, we can use the following equation for obtaining the relation between magnetic induction intensity and induced electromotive: B = ɛ n s ω (2) Fig. 8. Fig. 9. Placement of the coils Schematic diagram of driving circuit connected to the I/O port of computer through a photocoupler, and it is controlled by the signal output from the I/O port. When the SCR is ON, the electrical energy stored in C2 is transferred to the magnetic energy in the coil between A and B. When the current in the coil reaches zero, SCR will become OFF. The stimulation mode can be programmed before experiment (by C++), and after then, the magnetic stimulation will proceed automatically. In order to calculate the magnetic field of the multi-channel stimulator, a coil array of five coils was modeled by using the finite-element analysis software ANSYS, as each coil consid- III. RESULTS Results of human ANT stimulation studies [1], are talking about significant improvements with respect to the severity of the seizures when electrical current is applied on deep brain. Reduction of the total seizure frequency was demonstrated. Displaying the kind of waveforms outcome of this studies are not shown, because they are bot saying to us what we are looking for in terms of graphical representations. They are rather recordings of intracranial EEG (Electroencephalography) signals. In [2], stimulation applied on STN (Subthalamic Nucleus) in rats, resulted in the generation of excitatory postsypnatic potentials and an increase in action potential firing during the stimulation period, followed by a period of poststimulation inhibition of firing in STN neurons. It was demonstrated that, the degree of increase in action potentials was critically dependent on the frequency of electrical stimulation, and at approximately Hz, maximal increase was obtained, but at 200 Hz, the activity was blocked, what suggests us the latter as the frequency technical limit. Despite this fact, we are thinking in deep human brain stimulation and, some studies, like it written by J.F. Tellez-Zenteno et.al. [3], are centered in medial temporal lobe stimulation. Specifically, results in hippocampal electrical stimulation show

5 5 Fig. 11. Long-term seizure outcome (monthly seizures). RCT = randomized controlled trial; straight line = stimulator ON Fig. 13. Effects of subacute electrical stimulation of the hippocampal formation or gyrus (SAHCS) on seizures and interictal spikes in the group of patients with evident fast and slow antiepileptic responses. A: Avrage number of seizures/day. B: Average number of interictal spikes/10s at the epileptic focus recorded daily during 16 days of SAHCS in patients with fast and slow antiepileptic responses. Note that clinical seizures were abolished after day 6 of SAHCS, and the number of interictal spikes were progressively and significantly decreased from 80 to 40% after 5 days (p< 0.01), from 40 to 18% after 9 days (p< 0.001), and from 18 to 8% after 11 days (p< ) Fig. 12. Effect of subacute electrical stimulation of the hippocampal formation or gyrus (SAHCS) on seizures and interictal spikes in individual patients. A: Number of seizures/day. B: Percent of interictal spikes/10s at the epileptic focus recorded daily during 16 days of SAHCS. Data from different patients are indicated by different symbols listed at the right. Data from patients with fast and slow antiepileptic responses (n=7) are grouped at the top, and those with no evident responses (n=3) are shown in th bottom graph. Fast responses (n=5) were produced by continuous stimulation of either the anterior hippocampus close to the amygdaloid nucleus or anterior parahippocampal gyrus close to the entorhinal cortex. slow responses (n=2) were produced by continuous stimulation of either the medial hippocampus or the anterior perforate space. no responses (n=2) were produced following interruption of stimulation applied to the anterior parahippocampal gyrus, and no response at all was observed (n=1) with continuous stimulation out of the hippocampus. Note that the periods when SAHCS was interrupted or stimulation was applied out of the hippocampus are indicated by discontinuous horizontal lines and corresponding symbols (empty circles and crosses within circles or filled circles a significant reduction in seizures of 15%. As shown in Fig. 11,seizures improved upon starting the hippocampal electrical stimulation trial. Improvement has been sustained for 4 years, although breakthrough seizures occurred more frequently during the fourth year. We could also find good results in terms of seizure in some other studies centered in hippocampus electrical stimulation. In the report write by Velasco et.al. [4], in 7 of 10 patients whose stimulation electrode contacts were placed within the hippocampal formation, and who experienced no interruption in the stimulation program, SAHCS abolished clinical seizures and significantly decreased the number of interictal EEG (Electroencephalographic) spikes at the focus after 5 6 days. As shown in Fig. 12A and Fig. 13A, seizures were abolished after 6 day of SHCS. Interictal spikes were either completely blocked or significantly reduced from 4 to 11 days, as displayed in Fig. 12B and Fig. 13B. Among all locations tried, the most evident and fast antiepileptic responses were found in 5 patients whose stimulation contacts were located at either the anterior hippocampus close to the amygdaloid nuclei or the anterior parahippocampal gyrus close to the entorhinal cortex. That is indicated through a white arrow in Fig. 6 and Fig. 12A and Fig. 13B. Up to now, we can realize that electrical stimulation of the human brain could lead us to a seizure frequency reduction. In the studies mentioned above, this fact is clearly demonstrated, and it is corroborate when we go through the article write by Angelo Franzini et.al. [8], where after macrostimulation (stimulation parameters: 2.0mA; 90µs; 100Hz) it can be noted a significant reduction of the paroxysmal activity, showing an abrupt disappearance of epileptic spikes. Fig. 14 display the seizure frequency rates in 3 different patients, where can be

6 6 Fig. 14. Seizure frequency reduction rates in patients 1, 2 and 3 observed a 70% reduction in seizure frequency, and a total remission from epileptic status in the last one, as months went by. When pulse generator waveforms are implanted, some differences among the IPG models and the idealized waveforms assumed in previous theoretical and clinical studies can be noted [5], and they are greater at higher frequencies and longer pulse widths. As shown in Fig. 15, the waveform from each IPG differed from each other, and both differed from the programmed stimulation parameters represented by the idealized monophasic waveform. The magnitude of the IPG cathodic pulse was less than expected. If we take a view to Fig. 15, at 185Hz the programmed voltage voltage was set to 1V, whilst the Soletra has a pulse magnitude of approximately 0.6V, and the Kinetra was 0.8V. In the same way, the total charge injected during the cathodic pulse can be substantially lower than expected, and this results in increased threshold voltages for neural activation, as displayed in Fig. 16. At commonly used therapeutic stimulation settings (130Hz, 3V, 60µsec) this caused reductions in the volume of tissue activated relative to the monophasic waveform: 10% reduction for Soletra; 15% reduction for Kinetra. When voltage thresholds generated by the idealized monophasic waveforms to that of the Solera Fig. 15. Differences among waveforms. The time course of the stimulation waveforms. The waveforms differed in the magnitude of the cathodic pulse, the duration and amplitude of the anodic pulse, and the presence of decay in the plateau regions of the cathodic and anodic pulses. Displayed waveforms are from 1.0 V, 450µsec stimulation settings. Inset shows magnified view of the cathodic pulse waveforms, it is found an average difference of 9% [5]. However, the biphasic-idealized thresholds were within 2.2% of the idealized monophasic waveform thresholds. In contrast, the biphasic-reduced thresholds were within 2.9% of the Soletra waveform thresholds, what confirm us that the cathodic phase had a primary effect, whilst the anodic phase had a smaller secondary effect. To measure and control the TEED (Total Electrical Energy Delivered) by deep brain stimulation systems over an arbitrary period of time, a mathematical equation was found [6]: T EED = (voltage)2 frequency pulsewidth impedance Setting time to 1 second: T EED 1sec = voltage2 frequency pulsewidth impedance time (3) 1second (4)

7 7 Fig. 16. Differences among waveforms. The plots forming the rows of the figure are grouped by stimulation frequency. Charge injected during the cathodic phase of the stimulation waveform, and activation threshold voltages for axons located 3 mm from the axis of the deep brain stimulation electrode Optimizing deep brain stimulation settings will generate maximal clinical benefits at the lowest possible TEED, resulting in fewer stimulation-related complications and longer battery life. In Fig. 17 is displayed the path that was followed to obtain the TEED equation. Trials in magnetic stimulation were made in 4 cases, using different amount of stimulation coils (each one driving the same current), within a coil array of 5 coils. The 4 cases were described as m=1, m=2, m=3 and m=5, where m represents the total amount of stimulation coils. [7] As shown in Fig. 18, B decreases with the distance away from the coil s center increasing. B fell to 0.1T when the distance is 10mm away from the coil s endpoint. In Fig. 19 can be observed that, the point where x=6mm is the transition point. After it, the relative ratios are greater than 1, and hold rising. After transition point, when m (number of working coils) increases, B as well. Fig. 17. Deriving the equation for total electrical energy delivered by a deep brain stimulator. the equation can be easily derived using equations of basic electronics. The proof begins with a simple equation for energy and continues by substituting equivalent terms until an equation for energy is determined as a factor of the three adjustable stimulus parameters (voltage, frequency, and pulse width), the DBS (Deep Brain Stimulation) system-measurable parameter of impedance and an arbitrary time constant. DC = direct current; E = energy delivered; f = frequency; I = current; P = power ; pw = pulse width; s = seconds ; R = impedance; t = time; V = voltage IV. CONCLUSIONS As a conclusion of the deep brain stimulation existing studies, it could be said that, implantation of electrodes and electrical current delivered was well tolerated in the ANT case. Patients were unaware of the presence or absence of intermittently stimulation. Fig. 18. Relationship between B and corresponding distance away from central a endpoint

8 8 patient population, and these mentioned differences should be considered in multi-patient studies and patient programming. In this point, and as mentioned above, energy delivered to the brain must have a technical limit. Therefore, being aware of the existing TEED equation [6], more research need to be done in order to reach a maximal clinical benefit resulting in seizures activity reduction (or total suppression) with the fewer stimulation as possible. So, the danger of damaging brain tissue could be widely reduced. In relation to magnetic stimulation, depth is improved by increasing the number of working coils. A multi-channel magnetic stimulator may be used to stimulate the brain in an efficient way [7]. If we were be able to obtain an accurated equivalent circuit of deep brain stimulation, maximal benefit in patient could be obtained at the lowest delivered electrical charge by optimizing current parameters or DBS settings. Fig. 19. Relative ratio of B among multi-coil stimulation and single coil stimulation The changes in seizure severity and frequency, suggests us the necessity of further investigation in the deep brain stimulation for treatment of human diseases. The studies in animals (rats) [2] suggest that the mechanism of action of deep brain stimulation involves initial excitation followed by later inhibition of STN neurons at a cellular level. Other studies [9] have also demonstrated that highfrequency electrical stimulation (> 100 Hz) to STN could result in steady membrane depolarizations that triggered action potentials at a high rate followed by burst, and finally totally silenced cells. In the study of hippocampus electrical stimulation [3], we can conclude that seizure will be reduced through the delivery of an electrical current, but as suggested by Fig. 11, we don t really know if seizures will recover some months or years later the treatment is stopped. More research in this area is clearly needed. Moreover, applying SAHCS method in hippocampus stimulation [4], temporal lobe epileptogenesis could be blocked, with no obvious hippocampal damage attributable to the electrical stimulation. Through IPGs waveform method [5], tissue damages are avoid as mentioned in previous sections. Studies in this area, taught us that calculating charge or energy injected into the tissue during deep brain stimulation must be taken into account. Due to the differences between the ideal waveforms and these from IPGs, errors are created when calculating the voltage distribution in the tissue or the amount of charge or energy injected into it, overall at higher frequencies and longer pulse widths. So, developing computer models of deep brain stimulation should consider this interesting results. Moreover, the IPG model may be a source of variance within a V. PROPOSAL RESEARCH IN BRAIN STIMULATION Taking into account the valuable information got from several studies mentioned in this report, we could center our efforts in finding a good equivalent circuit, which represent in a proper way the deep brain stimulation. Using a programming language, a stimulation mode can be programmed and some results could be obtained when input parameters are modified, that would lead us to interesting outcomes. In such a way, electrical, electronic and programming subjects might be considered for reaching our goals. REFERENCES [1] R. S. F. S. C. J. A. F. D. E. B. M. D. a. S. G. B. J. J. S. K. M. A. B. M. R. John F. Kerrigan, Briant Litt and N. 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