Paul H Stypulkowski

Medtronic, Minneapolis, Minnesota, United States

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Publications (19)55 Total impact

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    ABSTRACT: Background The use of Deep Brain Stimulation (DBS) as a potential therapy for treatment resistant epilepsy remains an area of active clinical investigation. We recently reported the first chronic evaluation of an implantable, clinical-grade system that permits concurrent stimulation and recording, in a large animal (ovine) model developed to study DBS for epilepsy. Objective In this study we extended this work to compare the effects of remote (anterior thalamic) and direct (hippocampal) stimulation on local field potential (LFP) activity and network excitability, and to assess closed-loop stimulation within this neural network. Methods Following anesthesia and 1.5T MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted in three subjects using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and LFPs in response to thalamic and hippocampal stimulation were collected with the implanted device and analyzed off-line. Results Consistent with earlier reports, thalamic DBS and direct stimulation of the hippocampus produced parameter-dependent effects on hippocampal activity. LFP suppression could be reliably induced with specific stimulation parameters, and was shown to reflect a state of reduced network excitability, as measured by effects on hippocampal EP amplitudes and after-discharge thresholds. Real-time modulation of network excitability via the implanted device was demonstrated using hippocampal theta-band power level as a control signal for closed-loop stimulation. Conclusions The results presented provide evidence of network excitability changes induced by stimulation that could underlie the clinical effects that have been reported with both thalamic and direct cortical stimulation.
    Brain Stimulation 01/2014; · 4.54 Impact Factor
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    ABSTRACT: Deep brain stimulation (DBS) together with concurrent EEG recording has shown promise in the treatment of epilepsy. A novel device is capable of combining these 2 functions and may prove valuable in the treatment of epilepsy in dogs. However, stereotactic implantation of electrodes in dogs has not yet been evaluated. To evaluate the feasibility and safety of implanting stimulating and recording electrodes in the brain of normal dogs using the Brainsight system and to evaluate the function of a novel DBS and recording device. Four male intact Greyhounds, confirmed to be normal by clinical and neurologic examinations and hematology and biochemistry testing. MRI imaging of the brain was performed after attachment of fiducial markers. MRI scans were used to calculate trajectories for electrode placement in the thalamus and hippocampus, which was performed via burr hole craniotomy. Postoperative CT scanning was performed to evaluate electrode location and accuracy of placement was calculated. Serial neurologic examinations were performed to evaluate neurologic deficits and EEG recordings obtained to evaluate the effects of stimulation. Electrodes were successfully placed in 3 of 4 dogs with a mean accuracy of 4.6 ± 1.5 mm. EEG recordings showed evoked potentials in response to stimulation with a circadian variation in time-to-maximal amplitude. No neurologic deficits were seen in any dog. Stereotactic placement of electrodes is safe and feasible in the dog. The development of a novel device capable of providing simultaneous neurostimulation and EEG recording potentially represents a major advance in the treatment of epilepsy.
    Journal of Veterinary Internal Medicine 11/2013; · 2.06 Impact Factor
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    ABSTRACT: This paper introduces a new method for estimating the excitability of brain networks. The motivation for this research was to develop a system that can track pathological changes in excitability, in diseases such as epilepsy. The ability to track excitability may provide a method for anticipating seizures and intervening therapeutically. Four normally healthy canines were implanted with the Medtronic Activia PC+S deep brain stimulation and sensing system. The devices were used to probe the circuit of Papez, with electrical stimulation in the anterior nucleus of the thalamus to measure evoked potentials in the hippocampus. The canines were given three different dosage levels of anti-convulsant medication in an attempt to manipulate the excitability of the network. The results showed changes in the morphology of the evoked potentials, following a circadian profile and reflecting times of drug delivery.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 07/2013; 2013:6151-6154.
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    ABSTRACT: Modulation of neural activity through electrical stimulation of tissue is an effective therapy for neurological diseases such as Parkinson's disease and essential tremor. Researchers are exploring improving therapy through adjustment of stimulation parameters based upon sensed data. This requires classifiers to extract features and estimate patient state. It also requires algorithms to appropriately map the state estimation to stimulation parameters. The latter, known as the control policy algorithm, is the focus of this work. Because the optimal control policy algorithms for the nervous system are not fully characterized at this time, we have implemented a generic control policy framework to facilitate exploratory research and rapid prototyping of new neuromodulation strategies.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 07/2013; 2013:6146-6150.
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    ABSTRACT: Background/Aims: In conjunction with therapeutic stimulation, next-generation deep brain stimulation (DBS) devices may offer the ability to record and analyze neural signals, providing for unprecedented insight into DBS effects on neural networks. This work was conducted to evaluate an implantable, clinical-grade system that permits concurrent stimulation and recording using a large animal (ovine) model recently developed to study DBS for epilepsy. Methods: Following anesthesia and 1.5-tesla MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted (n = 3) using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and local field potentials were collected with the implanted device and analyzed off-line. Results: Hippocampal EPs were stable over long-term (>1 year) recording and consistent in morphology and latency with prior acute results. Thalamic and hippocampal DBS produced both excitatory and inhibitory network effects that were stimulation site and parameter dependent. Free roaming recordings illustrated periods of highly correlated activity between these two structures within the circuit of Papez. Conclusions: These results provide further insight into mechanisms of DBS therapy for epilepsy and an encouraging demonstration of the capabilities of this new technology, which in the future, may afford unique opportunities to study human brain function and neuromodulation mechanism of action.
    Stereotactic and Functional Neurosurgery 03/2013; 91(4):220-232. · 1.46 Impact Factor
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    ABSTRACT: Chronically implantable, closed-loop neuromodulation devices with concurrent sensing and stimulation hold promise for better understanding the nervous system and improving therapies for neurological disease. Concurrent sensing and stimulation are needed to maximize usable neural data, minimize time delays for closed-loop actuation, and investigate the instantaneous response to stimulation. Current systems lack concurrent sensing and stimulation primarily because of stimulation interference to neural signals of interest. While careful design of high performance amplifiers has proved useful to reduce disturbances in the system, stimulation continues to contaminate neural sensing due to biological effects like tissue-electrode impedance mismatch and constraints on stimulation parameters needed to deliver therapy. In this work we describe systematic methods to mitigate the effect of stimulation through a combination of sensing hardware, stimulation parameter selection, and classification algorithms that counter residual stimulation disturbances. To validate these methods we implemented and tested a completely implantable system for over one year in a large animal model of epilepsy. The system proved capable of measuring and detecting seizure activity in the hippocampus both during and after stimulation. Furthermore, we demonstrate an embedded algorithm that actuates neural modulation in response to seizure detection during stimulation, validating the capability to detect bioelectrical markers in the presence of therapy and titrate it appropriately. The capability to detect neural states in the presence of stimulation and optimally titrate therapy is a key innovation required for generalizing closed-loop neural systems for multiple disease states.
    IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society 01/2012; 20(4):410-21. · 2.42 Impact Factor
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    ABSTRACT: While modulating neural activity through stimulation is an effective treatment for neurological diseases such as Parkinson's disease and essential tremor, an opportunity for improving neuromodulation therapy remains in automatically adjusting therapy to continuously optimize patient outcomes. Practical issues associated with achieving this include the paucity of human data related to disease states, poorly validated estimators of patient state, and unknown dynamic mappings of optimal stimulation parameters based on estimated states. To overcome these challenges, we present an investigational platform including: an implanted sensing and stimulation device to collect data and run automated closed-loop algorithms; an external tool to prototype classifier and control-policy algorithms; and real-time telemetry to update the implanted device firmware and monitor its state. The prototyping system was demonstrated in a chronic large animal model studying hippocampal dynamics. We used the platform to find biomarkers of the observed states and transfer functions of different stimulation amplitudes. Data showed that moderate levels of stimulation suppress hippocampal beta activity, while high levels of stimulation produce seizure-like after-discharge activity. The biomarker and transfer function observations were mapped into classifier and control-policy algorithms, which were downloaded to the implanted device to continuously titrate stimulation amplitude for the desired network effect. The platform is designed to be a flexible prototyping tool and could be used to develop improved mechanistic models and automated closed-loop systems for a variety of neurological disorders.
    Frontiers in Neural Circuits 01/2012; 6:117. · 3.33 Impact Factor
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    ABSTRACT: We briefly describe a dynamic control system framework for neuromodulation for epilepsy, with an emphasis on its practical challenges and the preliminary validation of key prototype technologies in a chronic animal model. The current state of neuromodulation can be viewed as a classical dynamic control framework such that the nervous system is the classical "plant", the neural stimulator is the controller/actuator, clinical observation, patient diaries and/or measured bio-markers are the sensor, and clinical judgment applied to these sensor inputs forms the state estimator. Technology can potentially address two main factors contributing to the performance limitations of existing systems: "observability," the ability to observe the state of the system from output measurements, and "controllability," the ability to drive the system to a desired state. In addition to improving sensors and actuator performance, methods and tools to better understand disease state dynamics and state estimation are also critical for improving therapy outcomes. We describe our preliminary validation of key "observability" and "controllability" technology blocks using an implanted research tool in an epilepsy disease model. This model allows for testing the key emerging technologies in a representative neural network of therapeutic importance. In the future, we believe these technologies might enable both first principles understanding of neural network behavior for optimizing therapy design, and provide a practical pathway towards clinical translation.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:753-6.
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    ABSTRACT: This paper describes the preliminary technology validation of a bi-directional neural interface in an awake large animal model (ovine). The device addresses the major requirements of a chronic research system, including operation within the implantable environment and electrical stimulation with concurrent bioelectric sensing. Preliminary chronic measurements of network dynamics demonstrate that a chronically stable bi-directional interface to the nervous system is achievable. This was shown through chronic impedance and evoked potential measurements in the thalamo-cortical circuit of Papez. Characterization of bioelectric sensing in the presence of stimulation was also performed through measurements of the noise floor in the presence and absence of stimulation. Further technology validation was performed by using the prototype to correlate activity within and between structures in the circuit of Papez in the presence and absence of stimulation.
    Neural Engineering (NER), 2011 5th International IEEE/EMBS Conference on; 06/2011
  • Paul H Stypulkowski, Jonathon E Giftakis, Tina M Billstrom
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    ABSTRACT: To better understand the mechanism of action of deep brain stimulation (DBS) for epilepsy and to investigate implantable device features, it is desirable to have a large animal model to evaluate clinical-grade systems. This study assessed the suitability of an ovine model of epilepsy for this purpose. Animals were anesthetized for surgery and 1.5 T MRIs collected. Unilateral anterior thalamic DBS leads, hippocampal depth electrodes and catheters were implanted using a frameless stereotactic system. Evoked responses and local field potentials were collected and stored for off-line analysis. Despite limited neuroanatomic information for this species, it was possible to reliably implant leads into the target structures using MR-guided techniques. Stimulation of these regions produced robust evoked potentials within this circuit that were dependent on stimulus location and parameters. High-frequency thalamic DBS produced a clear inhibition of both spontaneous and penicillin-induced ictal activity in the hippocampus which far outlasted the duration of the stimulation. These preliminary results suggest that the sheep model may be useful for further investigation of DBS for epilepsy. The demonstration of marked suppression of network excitability with high-frequency stimulation supports a potential therapeutic mechanism for this DBS therapy.
    Stereotactic and Functional Neurosurgery 02/2011; 89(2):111-22. · 1.46 Impact Factor
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    ABSTRACT: We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.
    Biological psychiatry 11/2008; 65(4):267-75. · 8.93 Impact Factor
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    ABSTRACT: Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.
    Molecular psychiatry 06/2008; 15(1):64-79. · 15.05 Impact Factor
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    R.L. Testerman, M.T. Rise, P.H. Stypulkowski
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    ABSTRACT: This article outlines the basics of implantable neurological stimulators (INSs) and electrodes. Mechanisms of neural stimulation relevant to the clinician are reviewed, including the activating function, strength-duration relationship, and strength-distance relationship as well as safety considerations including safe charge and charge density levels. Clinical examples are taken from spinal cord stimulation (SCS) for pain and deep brain stimulation (DBS) for movement disorders such as essential tremor and Parkinson's disease
    IEEE Engineering in Medicine and Biology Magazine 10/2006; · 2.73 Impact Factor
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    ABSTRACT: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial. Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus. Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.
    Journal of Neurosurgery 05/2006; 104(4):558-65. · 3.15 Impact Factor
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    ABSTRACT: Measurements in phantoms are used to predict temperature changes that would occur in vivo for medical implants due to the radio frequency (RF) field in magnetic resonance imaging (MRI). In this study, the impact of concentration of the gelling agent in a saline-based phantom on the RF-induced temperature rise was measured using an apparatus that accurately reproduces the RF environment present in a 1.5-T whole-body MR system. The temperature was measured using fluoroptic thermometry at the electrode and other sites for a deep brain neurostimulation system. The average power deposition in the 30-kg phantom was about 1.5 W/kg. Four phantom formulations were evaluated, using different concentrations of polyacrylic acid (PAA) added to saline solution, with NaCl concentration adjusted to maintain an electrical conductivity near 0.24 S/m. The greatest temperature rises occurred at the electrode, ranging from 16.2°C for greatest concentration of PAA to 2.9°C for only saline solution. The temperature rise attained the maximal value for sufficient concentration of PAA. Similar behavior was observed in the temperature versus time relationship near a current-carrying resistor, immersed in gel and saline, which was used to model a localized heat source. The temperature rise for insufficient PAA concentration is reduced due to convection of phantom material. In conclusion, an appropriate gelling agent is required to accurately simulate the thermal properties of body tissues for measurements of RF-induced heating with medical implants.
    IEEE Transactions on Magnetics 10/2003; · 1.42 Impact Factor
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    ABSTRACT: In this paper we study the magnetic resonance imaging (MRI), eddy currents are induced in the body of the patient by the RF magnetic field. The precession rate of the proton magnetization determines the frequency, which is 64 MHz for 1.5 T static field. The RF-induced currents in the body are concentrated near medical implants, resulting in a localized additional temperature rise.
    01/2003;
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    ABSTRACT: PurposeTo assess magnetic resonance imaging (MRI)-related heating for a neurostimulation system (Activa® Tremor Control System, Medtronic, Minneapolis, MN) used for chronic deep brain stimulation (DBS).Materials and Methods Different configurations were evaluated for bilateral neurostimulators (Soletra® Model 7426), extensions, and leads to assess worst-case and clinically relevant positioning scenarios. In vitro testing was performed using a 1.5-T/64-MHz MR system and a gel-filled phantom designed to approximate the head and upper torso of a human subject. MRI was conducted using the transmit/receive body and transmit/receive head radio frequency (RF) coils. Various levels of RF energy were applied with the transmit/receive body (whole-body averaged specific absorption rate (SAR); range, 0.98–3.90 W/kg) and transmit/receive head (whole-body averaged SAR; range, 0.07–0.24 W/kg) coils. A fluoroptic thermometry system was used to record temperatures at multiple locations before (1 minute) and during (15 minutes) MRI.ResultsUsing the body RF coil, the highest temperature changes ranged from 2.5°–25.3° C. Using the head RF coil, the highest temperature changes ranged from 2.3°–7.1° C.Thus, these findings indicated that substantial heating occurs under certain conditions, while others produce relatively minor, physiologically inconsequential temperature increases.Conclusion The temperature increases were dependent on the type of RF coil, level of SAR used, and how the lead wires were positioned. Notably, the use of clinically relevant positioning techniques for the neurostimulation system and low SARs commonly used for imaging the brain generated little heating. Based on this information, MR safety guidelines are provided. These observations are restricted to the tested neurostimulation system. J. Magn. Reson. Imaging 2002;15:241–250. © 2002 Wiley-Liss, Inc.
    Journal of Magnetic Resonance Imaging 02/2002; 15(3):241 - 250. · 2.57 Impact Factor
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    ABSTRACT: Recent work has shown a potential for excessive heating of deep brain stimulation electrodes during MR imaging. This in vitro study investigates the relationship between electrode heating and the specific absorption rate (SAR) of several MR images. In vitro testing was performed by using a 1.5-T MR imaging system and a head transmit-receive coil, with bilateral deep brain stimulation systems positioned in a gel saline-filled phantom, and temperature monitoring with a fluoroptic thermometry system. Standardized fast spin-echo sequences were performed over a range of high, medium, and low SAR values. Several additional, clinically important MR imaging techniques, including 3D magnetization prepared rapid acquisition gradient-echo imaging, echo-planar imaging, quantitative magnetization transfer imaging, and magnetization transfer-suppressed MR angiography, were also tested by using typical parameters. A significant, highly linear relationship between SAR and electrode heating was found, with the temperature elevation being approximately 0.9 times the local SAR value. Minor temperature elevations, <1 degrees C, were found with the fast spin-echo, magnetization prepared rapid acquisition gradient-echo, and echo-planar clinical imaging sequences. The high dB/dt echo-planar imaging sequence had no significant heating independent of SAR considerations. Sequences with magnetization transfer pulses produced temperature elevations in the 1.0 to 2.0 degrees C range, which was less than theoretically predicted for the relatively high SAR values. A potential exists for excessive MR imaging-related heating in patients with deep brain stimulation electrodes; however, the temperature increases are linearly related to SAR values. Clinical imaging sequences that are associated with tolerable temperature elevations in the <or=2.0 degrees C range at the electrode tips can be performed safely within an SAR range <2.4 W/kg local (0.9 W/kg whole body averaged).
    American Journal of Neuroradiology 01/2002; 23(10):1795-802. · 3.17 Impact Factor
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    Roy L Testerman, Mark T Rise, Paul H Stypulkowski
    IEEE Engineering in Medicine and Biology Magazine 25(5):74-8. · 2.73 Impact Factor