Option to provide the necessary feedback for closed-loop neurostimulation

10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
Option to Provide the Necessary Feedback for Closed-Loop neuroStimulation Radu BAZAVAN1, Rodica STRUNGARU2 Faculty of Electronics, Telecommunications and Information Technology 1-3 Iuliu Maniu Av, Bucharest Abstract — Recent developments in Deep Brain Stimulation
subjected to MPTP neurotoxin. (DBS) and computer technology have resulted in dramatically
There was an improvement to the Globus Pallidus (GPi) new and effective surgical treatments for Parkinson's disease
as to be an effective target, giving back response with and other movement disorders. From the DBS, by research, the
disease effects release. Subthalamic Nucleus (STN) ended concept has evolved to Closed-Loop neuroStimulation (CLnS)
up being the best target solution in Deep Brain Stimulation which is the brain target point electric stimulation linked to the
patient's body and brain response.

One delicate CLnS difficulty in rising concept functionality
Other tremors offer favorable DBS reply, these including is contoured by the need of a feedback source.
Essential Tremor, Post Traumatic Tremor, Dystonias, even Regarding Parkinson's disease, the Subthalamic Nucleus (at
up to tremor resulting form multiple sclerosis. target point) generates a modulated signal by Parkison's
Recent developments in DBS and computer technology tremor. The amplitude values of the modulated signal envelope
have resulted in dramatically new and effective surgical are far most variable during the day.
treatments for Parkinson's disease and other movement By neurostimulating with a signal linked to the differences
disorders. From the DBS, by research, the concept has between maximum and minimum values of modulated signal
envelope provided, the patient will receive the exact values

evolved to Closed-Loop neuroStimulation (CLnS). This new required for Parkinson symptoms suppression.
CLnS concept is a highly active research area in neuromodulation science. Index Terms — Biomedical measurements, Closed-Loop
Still, DBS is the base application that lies below the neuroStimulation, Deep Brain Stimulation, DBS process, CLnS, that safely and effectively manages some of the most
disabling motor symptoms of Parkinson's disease, Essential Tremor, Dystonia and Epilepsy. DBS concept is defined as a medical device needed to be Parkinson's disease is a progressive brain disorder surgically implanted, aiming to provide highly controlled characterized by tremor, muscular rigidity and slowness of electrical signals and those transmissions to the brain. The movement (bradykinesia). Around 1945's, the surgery electrically stimulation is accomplished towards certain treatment has came to be a very good version characteristic brain structures that control muscular activity. For effects release of this disease. Using stereotactic guidance Parkinson's disease, those structures are the STN or GPi. technology, surgeons defined the basal ganglia as to be the portion of the brain responsible with the body's reaction Symptoms avoidance should occur by neurostimulation at regarding this issue, in which destructive lesions solution amplitudes between 1 and 4V, pulse widths of 60 to has improved the patients' healing and recovery, effectively 120μsec, and rates of 130 to 180Hz.providing reduced tremor and rigidity.
The CLnS concept of integrating the stimulator into the Introduction in 1960 of a new drug called levodopa (L- natural regulation system, instead of mimicking the dopa) reduced the method of Parkinson's disease treatement behavior, is expected to yield various clinical benefits. in stereotactic surgery. The L-dopa drug offered the power In Parkinson's disease case, the closed-loop stimulation to reduce the disease effects, giving to the diagnosed process starts by implantation of an electrodes array (2 to 5 Parkinson's disease patients the possibility by drug treatment unipolar/bipolar/quadripolar leads) that is intended to to have a life much close to the normal.
strongly localize the final target. An unwanted patient return symptom after a few years of The implantation of the leads requires stereotactic drug treatment rises a next reaction of writhing movements neurosurgical techniques for the initial implant and ongoing (dyskinesias) along with many other side effects. postoperative patient supervision. Following these drug treatment inconveniences for the Stereotactic surgery or stereotaxy is a minimally-invasive patients as well as the accelerated development of form of surgical intervention that makes use of a three-technology regarding stereotaxic solutions connected to CT dimensional coordinates system to locate small targets and RMN advanced imaging, stimulation treatment variant inside the body and to perform on them actions such as began to be seen as an increasingly better solution. Medical research scientists established high perceptions 1 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that causes permanent symptoms of Parkinson's disease by destroying of Parkinson's disease treatment after animals experiments certain neurons in the substantia nigra of the brain. 2 The use of rates less than 30 pps (pulses per second) may "drive " tremor, cause it to occur at the same frequency as the programmed frequency. For this reason, rates should not be given below 30 pps.

10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
ablation (removal), biopsy, stimulation, implantation, A. Indications. radiosurgery (SRS) etc. Bilateral brain neurostimulation is a Parkinson's control The three dimensions are latero-lateral (x), dorso-ventral therapy if the tremor together with all disease symptoms are (y) and rostro-caudal (z). an advanced daily events disability problems and work life This technique uses images of the brain to guide the limitation. The GPi or the STN is the target for this process. surgeon to a target within the brain. A colorful term for this Stimulation may also be considered as ancillary or surgery is neuro-navigation. An external frame attached to compensatory option against patient inadequate drug the head (frame-based) or imaging markers attached to the treatment response of L-dopa, also adding the unwanted scalp (frameless or image-guided surgery) are being used to appearance of body habits joined with raising medication orient the surgeon in his approach (Fig. 1, San Diego, dose levels. Neurosurgical Medical Clinic, Inc.). Unilateral thalamic neurostimulation is indicated for the upper area body tremor avoidance. This course is chosen for patients who were diagnosed with Parkinsonian tremor or Essential Tremor. B. Contraindications. Diathermy exposure (use of high-frequency electric current for deep heating of tissues in physical therapy, all now referred to as diathermy). Shortwave, ultrasound and microwave diathermy will heat the tissues at different Figure 1. Stereotactic frame-based, patient's fixation - left image, lead track
depths for different purposes. These may cause molecules in positioning - right image. deep tissue to vibrate, heating the tissues and increasing Target localization for stereotactic implantation of the blood flow to them. Low heat warms tissue and higher DBS lead is performed with the use of CT and/or MRI degrees will destroy tissue. Further, the diathermy therapy scans. For further localization of the target, test stimulation becomes energy conveyance to the implanted system, or mapping electrode may be used afterwards. causing tissue damage to implanted electrodes area, leading Neurosurgeons who use microelectrode recording in to serious trauma until death. Diathermy exposure it is also stimulation techniques may choose commercially available restricted causing additional neurostimulation system microelectrodes such as Medtronic, Radionics, Micro- components failure, forcing a new surgery to replace them, Neurode, FHC and microTargeting electrodes. Even on its reducing the proper evolution of the patient. Injury of benefits, it must also be taken into consideration that it is not patient and/or implanted system can occur during diathermy recommended for the DBS lead to be used for mapping. exposure whether the neurostimulation system is running or not. Magnetic Resonance Imaging (MRI) on the upper There are three commonly used surgical techniques for patient's body area wherein the impulse generator is usually located, advancing to brain where the lead electrodes are a) Ablation surgery is the minimally invasive implanted. mechanical unwished tissue removal. Represents Transcranial magnetic stimulation (TMS) is also a the medical procedure that neutralizes and restricted medical application. eliminates the harmful tissue making use of CLnS is not recommended for (Medtronic, et al.): laser or high radio frequencies causing heat, ¾ patients with neurological disease origins other coagulation and tissue death. Failure tissue than idiopathic; removal procedure will cause infection. ¾ patients with a previous surgical ablation b) Deep brain stimulation offers many advantages against ablative technique. The procedure is also ¾ patients under 18 years age; minimally invasive and there is no tissue ¾ patients beyond 75 years age; removal. The afterwards body response may be ¾ patients with dementia, coagulopathies, other modified considering that this technique is based psychiatric or neurologic disorders, including but on an electronic stimulator system implant with not limited to Tourette syndrome, depression, subsequent control. Bilateral STN stimulation obsessive compulsive disorder. can give the maximum desired effect with C. Location of stimulation. minimal side effects, opposite bilateral thalamus ablation which may cause undesirable results. For Parkinson's disease, stimulation settings for leads implanted in the GPi may be higher than stimulation settings Gamma Knife is a non-invasive technique that uses radiation to brain treatment and is often for systems implanted in the Subthalmic Nucleus (STN). called radiosurgery. The device aims gamma Consequently, systems implanted in the GPi may have radiation focus directly through a target point. shorter battery life than systems implanted in the STN.3) The present case study is DBS leading to CLnS, the two Target sites for Tremor Control Therapy and Parkinson's concepts will be individually detailed to reveal elements and 3 Clinical studies in neurostimulation for advanced Parkinson's disease, conclusions throughout this research. at least 58% of all subjects had identical rates bilaterally at all follow-up visits.

10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
Control Therapy include the ventral intermediate nucleus of the thalamus (Vim), and the STN or the GPi respectively. For further highlighting of Parkinson's disease brain areas, table 1 below (Medtronic, 2008) offers target sites and indication related. TABLE 1. TARGET SITES FOR PARKINSON'S DISEASE Target Site
Bilateral stimulation of the GPi or the STN is indicated for adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication. Unilateral thalamic stimulation is indicated for the suppression of tremor in the upper extremity. The system is intended for use in patients who are diagnosed with Essential Tremor or Parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability. If the Vim is the targeted nucleus, the desired stimulation effect is an obvious suppression of tremor. Other stimulation effects that may aid in placement of the lead, but may not be Figure 2. Parkinson's DBS system.
desirable, include paresthesia, especially in the hand and So what we have (Fig. 3) is an inflexible system that is around the mouth (Medtronic, et al. 2008). trying to control a highly variable as the brain like it is a plastic organ. III. OUTCOME OF COMPETITION For more than a decade, doctors have been implanting devices called deep-brain stimulators into patients with Parkinson's disease and stimulating a small area of their brains with low-voltage electrical pulses. The devices electrically stimulate the GPi or STN, a structure deep inside the brain, through four electrodes (Morgen E. Peck, et al. 2008). When electrical impulses hit the targeted cells, the tremors associated with Parkinson's disease subside. There are three hypotheses to explain the mechanisms of Figure 3. Present main neurostimulation process.
¾ Depolarization blockade. Electrical currents block the neuronal output at or near the electrode To change the situation existing today the main goal is to generally provide patient brain feedback signals to the ¾ Synaptic inhibition. This causes an indirect stimulator that will modify stimulation parameters, locations regulation of the neuronal output by activating and other factors that can have a profound effect on overall axon terminals with synaptic connections to system performance. neurons near the stimulating electrode; ¾ De-synchronization of abnormal oscillatory IV. DATA SETS AND SELF-REGULATION OF activity of neurons. CLOSED-LOOP NEUROSTIMULATION However, the quality of treatment greatly depends on how Leads are implanted as in DBS lead implanting well surgeons implant these electrodes. A misplaced lead procedure, using frame-based stereotactic surgery, a light-could stimulate surrounding tissue and cause changes in the weight frame that is attached to the patient's head using local patient's mood and cognition. anesthesia. The head is CT and/or MRI scanned to identify Such a positioning error was recently found to be a the target area in relationship with the external frame. leading cause of the therapy's failure. Even with a perfect Since both the frame-based and the target area are "seen" implant (Fig. 2, M. Cook, 2009), patients have only one in the images, the distance of the target from reference control parameter: open-loop device "on " or "off ". points on the frame-based can be measured in three After days to weeks, after implantation, the stimulator is dimensions. Surgical apparatus attached to the head frame- programmed using a small computer which communicates based can be adjusted to the 3D coordinates of the target, with the implanted stimulator by an external antenna. and can be accurately approached by the surgeon (Fig. 1). Usually several hours of programming are needed, requiring For an accurate approach a CT and MRI image fusion is close cooperation of the neurologist or neurophysiologist, also needed. This fusion is required to be made due to the with the patient and family. difference of resolution and information density that can be 4 The use of MRI is done before the CLnS system implantation, MRI procedures being necessary for stereotaxy. After implantation, as 2.1 b) mentioned, MRI will not be allowed. 10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
offered by each. The CT scan is the best procedure to use when visualizing bones or cancer, while the MRI is best used when examining the ligaments, tendons, tumors, blood vessels or hemorrhages. Since MRI yields more contrast than CT, when differentiating the bone, cartilages and the soft tissues, it will give more precise delineation of normal critical structures and more accurate definition of tissue volumes. Knowing that almost all types of tissue are present in the patient's head, both CT and MRI scans are recommended. Figure 4. Main CLnS process.
The fusion between them is the ideal way to localize target
In general, closed-loop control is preferred over open- with equally important aspect of defining the lead track for loop control for both physiological and technological to reach the target point. reasons. For example, there is a highly nonlinear In order to improve the route to the target point, two other relationship between the open-loop stimulation parameters coordinates are established in the calculation resulted from and the resulting behavior produced by stimulating. CT and MRI fusion, namely ARC and RING. These two Moreover, the relationship between electrical stimulation coordinates express the amount of coronal and sagittal arc, and the resulting patient's adaptive reaction is a time- giving surgeon a safe and accurate advance of the lead dependent relationship. In open-loop systems the patient electrodes to the target, without crossing certain brain must visually monitor the body changes produced by the volumes and by avoiding intersection with any blood stimulation and adjust the command signal accordingly, but making these adjustments is both difficult and tedious. With However we must have consideration that imaging data closed-loop feedback control however, the relationship from MRI introduces some geometric distortion because all between the input and output parameters can be magnetic fields possess inhomogeneities of the main field automatically regulated to provide a linear relationship and and non-linearities of magnetic field gradients and current to compensate for those effects which vary over time. effects. In general, system distortion is particularly A system that integrates neural recordings from implanted important for larger fields of view as this distortion tends to electrodes for DBS, and uses it to program the amplitude, increase with growing distance from the centre of the repetition rate, and duration of pulse generation of the CLnS magnet. Also MRI does not provide the necessary geometric stimulator. Another goal is to have a final component of the accuracy and physical information required in CT based 3D design, including the amplifier that connects to the treatment planning systems, such as electron density of body implanted electrodes, the data circuits, digital filters and tissues. Nor can MR image complex bone/air heterogeneity. microprocessor that decides if, how, and when to stimulate. This information is essential for patient dose calculation and The technical system designed by several neural for designing compensators and modulators to shape the engineering researchers (Fig. 5) must have a feedback from beam profile. Therefore, the unique information provided by the brain activity which can provide the data necessary to MRI studies must be registered to and then integrated with adjust the new signal values of stimulation. CT treatment planning data set (e.g. G. Sannazzari, 2002). Physicians must take into account that fusion of the two CT and MRI images offers all necessary data regarding target location as well as the lead route to target point, therefore, the corporate researchers have build a dedicated software program for this issue. Giving attention to inner stimulating system, looking into the past, there's been only one way to tell how patients are taking to the treatment: by monitoring behavior outcomes. But a better way to evaluate treatment is to ask the brain directly. In such a system, neuronal feedback would direct the timing, location, and intensity of subsequent stimulation and would suppress side effects that many patients suffer today. The solution is to have programmable device capable of stimulating and recording from the brain simultaneously. Figure 5. CLnS system block diagram.
The main process is to adjust stimulation parameters in The biggest problem is precisely this aspect. To close the close relationship with body behavior prominent derived circuit and make the whole system work according to the from neural transmission in the brain. patients' feedback. Several ideas have been studied and DBS system is defined by its relationship with the patient discussed (e.g. Neural Interfaces Workshop, Bethesda, as an Open-Loop control system (Fig. 3). Since the CLnS 2005), bottom-line being feedback control system that was system has no patient intervention during the therapy action, is defined as the expression title a Closed-Loop control system (Fig. 4). Only if acceptance has been given by the physician in order to adjust the patient's stimulator actions/parameters. 6 Only if the DBS system manufacturer provides patient's directly parameters adjustments. 10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
identified as one of the major challenges confronting the Closed-Loop neuroStimulation concept is the ideal DBS industry in years to come. solution, but having present research treated irregular aspect. Knowing that one of the means to detect the target point The elementary source of feedback information from the is associated with signal analysis obtained during electrode body that may be part of this wonderful neuro solution, advancing to target point, its path must be a way to get responds to the entire package of variables. Regarding this information on what interests us. option to provide the necessary parameters for CLnS, the We must consider that the implanted leads normally used technical system can give maximum applied efficiency as for DBS implant are in contact with the target point. In intended. surgery, one of the ways to know that the target point is Using as feedback source the modulated carrier signal reached is to monitor the signal collected from the implanted envelope, the information provided by it can be used as lead. The entire lead implantation process is made with a functionality feedback to successfully close the CLnS micromotor device added to patient's head mounted system. stereotactic frame-based and carefully physician's real time signal monitoring during lead advance. The signal of the lead on the way to target point is a linear sampled signal It eliminates the patient interaction with the which does not give any dates on the patient's Parkinson's neurostimulation control system. disease or his condition regarding this issue. It prevents adverse reactions and bad condition of the Exact time of arrival of the lead on target point forces patient when the neurostimulator generates same linearly dissimilar signal receiving unlike any up to that moment. identical values when the disease has temporarily fallen The STN gave forth a modulated signal in 90 up to 95% of reactions. the cases a modulated signal.Additional comments 7.2) Having the It gives an optimal stimulation closely connected to the lead to target point, the signal provided by it can be used as patient's brain response. feedback information to functionally close the CLnS system.
It avoids the potential risk of brain tissue damage by The carrier signal can difference between 200Hz to stimulation parameter settings of high amplitudes and wide surprisingly high frequencies around 300Hz. This signal is pulse widths. modulated in amplitude by Parkinson's tremor frequency. It prolongs battery longevity of the impulse generator; etc. The modulation signal (i.e. Parkinson's tremor) has mostly 3Hz to 6Hz frequency value, with occasionally peak to 7- VII. ADDITIONAL COMMENTS / REMARKS If the carrier signal modulated by Parkinson's tremor 7.1 Regarding neurosurgeons implanting activity, the signal is converted to an envelope signal, we can easily CLnS impulse generator (pacemaker) must be implanted further obtain the minimum and maximum values of the away from bony structures and muscle tissue to minimize modulation amplitude. pain at the pacemaker site. This also helps to minimize the The amplitude values of the modulated signal envelope possibility of skeletal muscle stimulation. For connections, are variable during the day, related to patient's psychological the surgeon has to wipe off any body fluids on the extension condition and its body composition given by nutrition, or lead contacts or connector before connecting. temperature, etc. The STN signal provided through the lead Contamination of connections can cause intermittent electrodes is shown below, in Figure 6. stimulation or shorts in the neurostimulation circuit Giving the fact that the difference of maximum and (Medtronic, Soletra, 2003). minimum amplitude value is variable, this variation is the 7.2 High frequency test stimulation is a standard key required to adapt the stimulation signal parameters on procedure for target localization in deep brain stimulation CLnS in reaction to patient's brain response. treatments of patients with tremor. However, this method does not work in cases where the tremor disappears under global anesthesia as well as it is used during insertion of an electrode. To avoid this problem a new stimulation technique has been developed that evokes tremor in a well-defined manner even when the patient is under anesthesia. This technique uses patterned low-frequency stimulation in the form of brief high-frequency pulse trains applied at pulse rates similar to typical neuronal burst frequencies. This makes it possible to attain higher charge densities in the target area without violating safety criteria. Numerical simulations of a network of interacting neurons have shown that patterned low-frequency stimulation can synchronize the cells in a mode that is phase-locked to the stimulation Figure 6. STN modulated carrier signal.
pulse. When subsequently applying this approach to patients with pronounced tremor, the results were found to be in accordance with the mathematical calculations, and the The CLnS alter brain stimulation parameters according to target selection was confirmed by excellent postoperative recordings from the brain. tremor suppression (BioSim Group at the Jülich Research Centre, Aug. 2009). 10th International Conference on DEVELOPMENT AND APPLICATION SYSTEMS, Suceava, Romania, May 27-29, 2010
Disorders", Neurophysiology in Neurosurgery: A Modern Intraoperative Approach, Chapter 16, Elsevier Science, 2002. The success of this research came through the entire [7] G. L. Sannazzari, R. Ragona, M. G. Ruo Redda, G. Isolato, A medical support of neurosurgeon Jean Ciurea, MD, whom Guarneri, F. R. Giglioli, "CT–MRI image fusion for delineation of we are indebted. volumes in three-dimensional conformal radiation therapy in the treatment of localized prostate cancer", The British Journal of Special thanks for the research oversight and review Radiology, 75, 603–607, 2002. given by technical advisor Andrei Barborică, Eng. [8] William D. Hutchinson, "Techniques of Microelectrode Recording in Movement Disorders Surgery", Surgery for Parkinson's Disease and Movement Disorders, Philadelphia, 2001. [9] James Solberg, Richard Smith, "Closed-Loop Control of Functional [1] Xiao-jiang Feng, Eric Shea-Brown, Brian Greenwald, Herschel Electrical Stimulation for Human Gait: Introduction, Feedback Rabitz, Robert Kosut, "Toward Closed-Loop Optimization of Deep Sensors, and Foreseeable Difficulties", School of Electrical and Brain Stimulation for Parkinson's Disease: Concepts and Lessons Information Engineering, Nov. 2000. from a Computational Model", J.Neuroengineering 4, L14-L21, 2007. [10] R.E. Gross, A.M. Lozano, "Advanced in neurostimulation for [2] Michael Flynn, Daryl Kipke, "Single-Chip Closed-Loop Deep-Brain movement disorders", Neurol, Res., 22:247-258, 2000. Stimulation for Treatment of Parkinson's Disease" University of [11] Medtronic Inc., Research, Analysis, Trials, 2007-2010, Available: Michigan Research Update, Oct. 2009. [3] Jongwoo Lee, Hyo-Gyuem Rhew, Daryl Kipke and Michael Flynn, "A 64 Channel Programmable Closed-loop Deep Brain Stimulator [12] FHC Inc., Research, Analysis, Trials, 2010, Available: http://www.fh- with 8 Channel Neural Amplifier and Logarithmic ADC", Symposium co.com/research.html on VLSI Circuits Digest, 2008. [13] Neurosurgical Medical Clinic, "Movement Disorders Treatment: [4] Karen L. Francis, Waneen W. Spirduso, Tim Eakin, Pamela Z.New, Neurosurgical Medical Clinic Program", 2010, Available: "Long-Term Effects of ThalamicDeep Brain Stimulation on Force Control in a Patient with Parkinson's Disease-Driven Action Tremor", [14] Morgen E. Peck, "A Chip to Better Control Brain Stimulators for The Journal of Applied Research, Vol.6, No. 1, 2006. Parkinson's", June 2008, Available: http://spectrum.ieee.org/ [5] Thuy-Duong Barbara Nguyen-Vu, Hua Chen, Alan Cassell, Jessica Koehne, Hardeep Purewal, M. Meyyappan, Russell Andrews, and Jun Li, "Carbon Nanofiber Nanoelectrode Array for Closed-Loop [15] G.K.M. Fauser, P.J.P. Kuijer, "Closed Loop Stimulation in Patients Electrical Stimulation", Center for Nanotechnology, NASA Ames with Normal and Limited Contractility", Progress in Biomedical Research Center, Moffett Field, CA, Jul. 2005. Research, Apr. 1999. [6] Jay L. Shils, Michelle Tagliati, Ron L. Alterman, "Neurophysiological Monitoring During Neurosurgery for Movement

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