US20110184487A1 - Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming - Google Patents

Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming Download PDF

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US20110184487A1
US20110184487A1 US12/986,735 US98673511A US2011184487A1 US 20110184487 A1 US20110184487 A1 US 20110184487A1 US 98673511 A US98673511 A US 98673511A US 2011184487 A1 US2011184487 A1 US 2011184487A1
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dbs
motor
stimulation
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cognitive
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Jay L. Alberts
Cameron C. McIntyre
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Cleveland Clinic Foundation
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36103Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/05Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526Head electrodes
    • A61N1/0529Electrodes for brain stimulation
    • A61N1/0534Electrodes for deep brain stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36067Movement disorders, e.g. tremor or Parkinson disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128Control systems
    • A61N1/36135Control systems using physiological parameters

Abstract

A system and method may provide for conducting a stimulation of anatomic regions to treat a neuromotor, neurocognitive or neuromotor and neurocognitive disorder, according to which stimulation, motor regions are stimulated, while creep of current to non-motor regions is minimized. Stimulation parameters may be selected based on tests of motor function, tests of cognitive function, and tests of a combination of motor and cognitive functions.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • The present application is a continuation-in-part application of International Patent Application No. PCT/US10/58770, filed Dec. 2, 2010, which claims priority to U.S. Provisional Patent Application No. 61/265,782, filed Dec. 2, 2009, the entire contents of each of which is hereby incorporated by reference herein.
  • GOVERNMENT RIGHTS
  • Using the specific language required by 37 C.F.R. §401.14(f)(4): This invention was made with government support under grant numbers R01 NS058706 and R01 NS059736 awarded by the National Science Foundation. The government has certain rights in the invention.
  • FIELD OF THE INVENTION
  • The present invention relates to a system and method for stimulating anatomic regions and/or for selecting parameters for such stimulation.
  • BACKGROUND
  • Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and other forms of neuromodulation are effective and safe surgical procedures that have been shown to reduce the motor dysfunction of advanced Parkinson's disease (PD) patients. Bilateral DBS refers to stimulation on both sides of the brain, while unilateral DBS refers to stimulation on one side of the brain. Bilateral and unilateral DBS typically target one of three areas, including the STN, GPI, VIM. Bilateral STN DBS has been associated with declines in cognitive and cognitive-motor functioning. DBS is similarly used to treat other neuro-degenerative diseases including cognitive, motor, and cognitive-motor disorders, but presently used stimulation parameters result in detrimental side effects.
  • SUMMARY
  • Activities of daily living are typically performed under modestly complex conditions and have cognitive and motor components that are performed simultaneously (Cahn-Weiner, D. A. et al., “Tests of executive function predict instrumental activities of daily living in community-dwelling older individuals,” Appl. Neuropsychol. 9, 187-91 (2002) (hereinafter “Cahn-Weiner et al., 2002”), the entire contents of which is hereby incorporated by reference herein). Frontal and executive dysfunction in the elderly and PD patients without DBS can be predictive of cognitive and motor function during ADLs (Cahn-Weiner et al., 2002; Cahn, D. A. et al., “Differential contributions of cognitive and motor component processes to physical and instrumental activities of daily living in Parkinson's disease,” Arch Clin Neuropsychol. 13, 575-83 (1998) (hereinafter “Cahn et al., 1998”), the entire contents of each of which is hereby incorporated by reference herein). Understanding how PD and DBS impact cognitive and motor function under conditions requiring greater cognitive rigor and during the simultaneous performance of cognitive and motor tasks may provide a more accurate assessment of the effect of a set of stimulation parameters on cognitive and motor performance when patients are completing “real world” tasks. Current methods of assessing cognitive and motor function in a clinical environment may not be sufficiently demanding or sensitive enough to reveal changes in cognitive or motor performance that occur when either component of a task is increased. There is an emerging body of literature indicating a paradox between the clinical improvements in motor functioning associated with STN DBS and the patient and caregiver's level of postoperative satisfaction (Agid, Y. et al., “Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so?,” J. Neural Transm. Suppl. 409-14 (2006); Schupbach, M. et al., “Neurosurgery in Parkinson disease: a distressed mind in a repaired body?,” Neurology 66, 1811-6 (2006) (hereinafter “Schupbach et al., 2006”); Schupbach, M. et al., “Psychosocial adjustment after deep brain stimulation in Parkinson's disease,” Nature Clinical Practice 4, 58-59 (2008) (hereinafter “Schupbach and Agid, 2008”), the entire contents of each of which is hereby incorporated by reference herein).
  • Spread of current to non-motor areas of the STN may cause declines in cognitive and cognitive-motor functioning. A study was performed to assess and compare the cognitive-motor performance in advanced PD patients with bilateral STN DBS parameter settings determined clinically (Clinical), e.g., by subjective assessment such as asking a patient how the patient feels or observation of side effects due to stimulation, and with bilateral STN DBS parameter settings derived from a patient-specific computational model (Model), according to which current creep to non-motor regions was minimized or removed altogether. In this regard, the conventional method of parameter selection did not contemplate consideration of reduction of current creep to non-motor regions, but rather were selected largely on the subjective clinical measures, such that if one or more symptoms improved to some degree and there was no side effect noticed, then the parameters associated with those results were deemed worthy of use, without consideration of effect on creep to the non-motor regions. It was also conventionally not known that the spread of current to non-motor regions would negatively affect motor skill.
  • In the study, data were collected from 10 advanced PD patients, off medication, under three DBS conditions: OFF, Clinical and Model based stimulation. Clinical stimulation parameters had been determined based on clinical evaluations and the parameters were stable, i.e., unchanged, for at least six months prior to study participation. Model based parameters were selected to minimize the spread of current to non-motor portions of the STN using Cicerone DBS software (See Miocinovic S. et al., “Cicerone: stereotactice neurophysiological recording and deep brain stimulation electrode placement software system,” Acta Neurochir Suppl., 97, 561-7 (2007) (hereinafter “Miocinovic et al., 2007”), which is incorporated by reference herein). That is, in the study, and according to an example embodiment of the invention, software is used that provides a 2D or 3D visualization of patient images, DBS electrodes, and/or calculated estimated/predicted volumes of activation for specified stimulation parameters. Based on those visualizations, an operator is able to modify the parameters until a VTA is provided that has minimal current spread to non-motor portions of the brain. In fact such visualization and tinkering until selection of parameters for use may be performed without the presence of the patient.
  • For each stimulation condition (OFF, Clinical, and Model), participants performed a working memory (n-back task) and motor task (force-tracking) under single- and dual-task settings. During the dual-task, participants performed the n-back and force-tracking tasks simultaneously. Clinical and Model parameters were equally effective in improving the Unified Parkinson's disease Rating Scale (UPDRS-III) scores relative to Off DBS scores, e.g., with respect to motor response as measured by the UPDRS-III. The average improvement in off medication UPDRS-III scores for both parameter settings, 46 percent, is within the range of improvement typically reported in long-term studies with bilateral STN DBS in advanced PD patients (Abelson, J. L. et al., “Deep brain stimulation for refractory obsessive-compulsive disorder,” Biol Psychiatry. 57, 510-6 (2005); Kumar, R. et al., “Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor,” Neurology. 61, 1601-4 (2003); Rodriguez-Oroz, M. C. et al., “Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up,” Brain 128, 2240-9 (2005); Weaver, F. M. et al., “Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial,” Jama. 301, 63-73 (2009), the entire contents of each of which is hereby incorporated by reference herein). The inventors discovered that the n-back and force-tracking tasks, administered as described herein to obtain the test results described herein, provide a better context in which activities of daily living are completed, as most ADLS have a cognitive and motor component, and therefore provide a better measure than UPDRS for determining effectiveness of stimulation parameters.
  • Single-task working memory declines, in the 2-back condition, were significantly less under Model compared to Clinical DBS settings. Under dual-task conditions, force tracking was significantly better with Model compared to Clinical DBS. These results indicate that the cognitive and cognitive-motor declines associated with bilateral STN DBS may be reversed, without compromising motor benefits, by utilizing stimulation parameters that minimize current spread into non-motor regions of the STN. Theoretically, it is conceivable that there may be a task that is 100% motor related, without any cognitive function required, in which case it may occur that there would be no performance difference between Clinical and Model parameters, but almost no ADLs are purely motor.
  • Indeed, the transmission of pathological information within the basal ganglia thalamocortical circuits is thought to underlie the symptoms of PD (Albin, R. L. et al., “The functional anatomy of basal ganglia disorders,” Trends Neurosci 12, 366-375 (1989); DeLong, M. R., “Primate models of movement disorders of basal ganglia origin,” Trends. Neurosci. 13, 281-285 (1990); Llinas, R. R. et al., “Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography,” Proc. Natl. Acad. Sci. U.S.A. 96 (1999); Timmermann, L. et al., “The cerebral oscillatory network of parkinsonian resting tremor,” Brain 126, 199-212 (2003); Vitek, J. L. et al., “Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia,” Ann. Neurol. 47, S131-S140 (2000), the entire contents of each of which is hereby incoporated by reference herein). It is believed that DBS acts to regularize activity within the motor circuit thereby reducing the passage of pathological information from the pallidum (Grill, W. M. et al., “Deep brain stimulation creates an informational lesion of the stimulated nucleus,” Neuroreport 15, 1137-40 (2004); Guo, Y. et al., “Thalamocortical relay fidelity varies across subthalamic nucleus deep brain stimulation protocols in a data-driven computational model,” J Neurophysiol. 99, 1477-92 (2008); Hashimoto, T. et al., “Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons,” J Neurosci. 23, 1916-23 (2003), the entire contents of each of which is hereby incoporated by reference herein). The spread of current to non-motor regions of the STN is likely to disrupt the spread of non-pathological information from these non-motor regions of the STN. Disruption of information processing in these non-motor regions may be responsible for the DBS related cognitive-motor declines observed under dual-task conditions. The loss of transmitted information or information processing capabilities may not produce a deficit in cognitive function following unilateral procedures (Alberts, J. L. et al., “Bilateral subthalamic stimulation impairs cognitive-motor performance in Parkinson's disease patients,” Brain 131, 3348-60 (2008) (herein after “Alberts et al., 2008”), the entire contents of which is hereby incporperated by reference) or when the patients are able to focus all of their attention on the performance of a cognitive or motor task alone, as is the case during most clinical examinations. However, as the cognitive demands of the task increase, information processing demands increase. Therefore, under bilateral STN DBS with conventional Clinically determined stimulation parameters, which results in spread of current to non-motor regions, such current spread may compromise cognitive-motor functioning. Cognitive resources on which patients may attempt to draw may now be even more compromised as a result of bilateral disruption of non-motor pathways. The Model parameters according to the present invention, set to avoid spread to non-motor regions may minimize or avoid such further degeneration of cognitive resources.
  • Further in this regard, the focus of clinical programming has been on the motor response, and unless non-motor side effects are readily apparent, they are generally not detected; particularly those that may only arise under more complex testing conditions. In turn, unintentional over-stimulation can occur when the stimulus amplitude at a therapeutic contact is adjusted to be just below threshold for motor side effects, related to assumption that more stimulation is better than less. However, the study conducted by the inventors indicates that Model parameters resulted in similar improvements in clinical ratings and minimized cognitive-motor declines under dual-task conditions compared to Clinical settings, while using significantly less power (cf Table 4 below). Model parameters were selected to both focus a volume of tissue activated (VTA) on the target region and to be energy efficient. Previous clinical studies have found no significant benefit from using stimulation frequencies greater than 100-130 Hz (Moro, E. et al., “The impact on Parkinson's disease of electrical parameter settings in STN stimulation,” Neurology 59, 706-13 (2002) (hereinafter “Moro et al., 2002”; Rizzone, M. et al., “Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: effects of variation in stimulation parameters,” J. Neurol. Neurosurg. Psychiatry 71, 215-9 (2001), the entire contents of each of which is hereby incorporated by reference herein), and from the biophysical perspective of axonal activation the most energy efficient pulse width available in the Medtronic Soletra/Kinetra DBS system is 60 μs in a monopolar configuration (Butson and McIntyre, 2007; Sahin, M. et al., “Non-rectangular waveforms for neural stimulation with practical electrodes,” J. Neural Eng. 4, 227-33 (2007), the entire contents of each of which is hereby incoporated by reference herein). Therefore, the Model DBS parameters according to the present invention may be selected with these constraints, resulting in reduced power consumption that could help to minimize the threat of stimulation induced tissue damage and prolong battery life expectancy.
  • In addition to better overall cognitive-motor performance associated with Model parameters, the amount of power consumed was, on average, less than half of the Clinical settings.
  • Although the present invention is described in relation to Parkinson's Disease and the STN, the methods and systems of the present invention can be used by patients suffering from medical disorders. In preferred embodiments, the medical disorders are characterized by abnormal motor function, such as in patient's limbs (upper and/or lower extremities). The medical disorder can be a neurological disorder (i.e., a disorder of the patient's nervous system). In certain embodiments, the neurological disorder is a neuromotor or neurocognitive disorder that results in abnormal motor function and that is characterized by irregular motor cortical output including, for example, output from the cerebellum and/or supplementary motor area (“SMA”) of the cortex; and irregular sub-cortical output from regions that contribute to motor function in a patient such as, for example, the basal ganglia, the subthalamic nucleus and/or the thalamus.
  • The methods have application to mammalian patients, including humans suffering from the above-described disorders. In certain embodiments, the neuromotor or neurocognitive disorders are degenerative in nature. Exemplary disorders include PD, Alzheimer's Disorder, dementia, Parkinsonian syndrome, essential tremor, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, multiple system atrophy (MSA), and dystonia.
  • Embodiments of the present invention are directed to a system and method for stimulating an anatomical region in a stimulation procedure in which less than 10% of non-motor regions (i.e., regions not associated with motor function), e.g., of the brain, are stimulated. In an example embodiment, one or more of the zona incerta, lenticular fasciculus, and motor region of the globus pallidus and internal capsule are stimulated, while less than 10% of non-motor anatomical-neural regions of the globus pallidus or STN are stimulated.
  • In an example embodiment of the present invention, an anatomical region is stimulated in a stimulation procedure in which at least one of the zona incerta, lenticular fasciculus, and motor region of the globus pallidus and internal capsule are stimulated, while current is not spread to, and therefore there is no stimulation of, any of the corticospinal tract (CS), corticobulbar tract (CB), and the non-motor regions of the globus pallidus (GP) and internal capsule.
  • For example, a target VTA may be created, for example, according to methods described in U.S. patent application Ser. No. 12/266,394, entitled “3D Atlas Fitting Using MicroElectrode Recordings” and filed Nov. 6, 2008, in U.S. Provisional Patent Application Ser. No. 61/120,006, entitled “System and Method to Define Target Volume for Stimulation in the Brain” and filed Dec. 4, 2008, in International Patent Application No. PCT/US09/066821 entitled “System and Method to Define Target Volume for Stimulation in the Brain” and filed Dec. 4, 2009, in U.S. patent application Ser. No. 12/869,159, entitled “System and Method to Estimate Region of Tissue Activation” and filed Aug. 26, 2010, and in International Patent Application No. PCT/US 1046772, entitled “System and Method to Estimate Region of Tissue Activation” and filed Aug. 26, 2010, the entire contents of each of which is hereby incorporated by reference in its entirety, such that they include no or minimal spread of current to the non-motor regions.
  • Example embodiments of the present invention are directed to a system and method for selection of stimulation parameters for treatment of neuro-degenerative disorders, such as neuro-cognitive and/or neuro-motor disorders based on results of tests of cognitive function, tests of motor function, and a combination of such tests, performed by the patient to which stimulation is to be performed using the selected stimulation parameters. The stimulation may be performed using implanted electrodes. In an example embodiment, the test results may be used for selection of stimulation parameters that minimize creep of current to non-motor anatomic regions, e.g., of the brain. In an example embodiment, the n-Back test may be used as the test for testing cognitive function, a force-maintenance task may be used as the test for testing motor function, and a test where a patient is subjected to both the n-Back test and the force-maintenance task simultaneously may be used as the combination as a “dual task.”
  • In alternative example embodiments of the present invention, the motor and cognitive testing discussed throughout the present application may be performed using motor, cognitive, and/or motor-cognitive tests described in U.S. Provisional Pat. App. Ser. No. 61/262,662, filed Nov. 19, 2009 (“the '662 application”) and/or in International Pat. App. No. PCT/US10/57453, filed Nov. 19, 2010 (“the '453 application”), the entire contents of each of which is hereby incorporated by reference herein. Those tests may be administered and the test results captured and recorded, for example, as described in the '662 application and/or the '453 application.
  • U.S. Provisional patent Application No. 61/409,693, entitled “Improving Postural Stability with STN DBS” and filed Nov. 3, 2010, the entire contents of which is hereby incorporated by reference in its entirety describes further application and details of the features described herein concerning stimulation parameters selected for minimizing spread of current to and stimulation of non-motor anatomical regions.
  • Example embodiments of the present invention are directed to a computer system configured to determine stimulation parameters based on the above-described tests, e.g., to minimize creep of current to non-motor anatomical regions. That is, to determine stimulation parameters, the system may evaluate various parameter settings using objective and quantitative test that have cognitive and motor components.
  • Programming DBS devices for maximal clinical benefit and minimal side effects can be a difficult and time consuming process, requiring a highly trained and experienced individual to achieve desirable results (Hunka, K. et al. “Nursing time to program and assess deep brain stimulators in movement disorder patients,” J. Neurosci. Nurs. 37, 204-10 (2005); Moro, E. et al., “Subthalamic nucleus stimulation: improvements in outcome with reprogramming,” Arch. Neurol. 63, 1266-72 (2006) (hereinafter “Moro et al., 2006”), the entire contents of each of which is hereby incoporated by reference herein). While guidelines exist on stimulation parameter settings that are typically effective (Moro et al., 2002; Rizzone et al., 2001; Volkmann, J. et al., “Basic algorithms for the programming of deep brain stimulation in Parkinson's disease,” Mov. Disord. 21 Suppl. 14, S284-9 (2006), the entire contents of each of which is hereby incorporated by reference herein), these vary from patient to patient and it is not practical to clinically evaluate each of the thousands of stimulation parameter combinations that are possible in order to optimize DBS in each patient. As a result, the therapeutic benefits achieved with DBS are strongly dependent on the intuitive skill and experience of the clinician performing the programming (Moro et al., 2006) and the amount of time each programmer can allocate to that patient.
  • Rather than relying solely on intuition and experience, clinical DBS programming according to the present invention can be augmented with visualization of electrode location and theoretical calculation of an optimal VTA. Software technology can provide an initial starting point for the clinical programming process, thereby focusing patient testing on a select range of stimulation settings where an abbreviated version of the dual-task paradigm could be performed to evaluate cognitive and motor function. For example, the VTA may be visualized before the programming user even sees the patient. The programming user can essentially test a host of parameter sets using the software rather than having to actually apply those parameters to stimulation of the patient. The parameters that are most likely ineffective may therefore be eliminated to begin with. Additionally, the software itself may be programmed with parameter sets that are most likely ineffective due to, for example, current creep to non-motor regions, and may accordingly output suggested sets of parameter settings. The dual-task paradigm could concentrate clinical resources on maximizing clinical outcomes and minimize time consuming searches through the DBS parameter space (contact, voltage, pulse width, frequency).
  • According to an example embodiment of the present invention, cognitive and motor performance may be evaluated simultaneously, e.g., by administering the above-described tests, during DBS programming while visualizing VTAs associated with specific DBS parameters. This may mitigate the described paradoxical situation between the clinical improvements in motor functioning and the patient and caregiver's level of postoperative satisfaction. That is, by modifying DBS parameters based on the test results, the patient satisfaction to the DBS programming using the resultant stimulation parameters may be consistent with the motor benefits.
  • In this regard, by visualizing the various VTAs while simultaneously assessing the cognitive and motor performance as described herein, the medical clinician may be able to rank various VTAs according to such performance and modify the target VTAs until stimulation parameters are provided for a closely matching estimated VTA that produces the best cognitive and motor performance. The clinician may input notes in association with VTAs, which notes identify and/or rank the assessed cognitive and motor performance. The system may include a graphical user interface (GUI) that displays an anatomical model, e:g., of the patient brain and implanted leadwire, that further displays with respect to the displayed model one or more areas corresponding to explored VTAs, and that further displays note icons representing the input notes associated with such VTAs and displayed such that it is indicated with which VTAs the corresponding notes are associated. Responsive to selection of the note icons, the system and method may display the notes.
  • According to an example embodiment of the present invention, the clinician may input a score associated with the explored VTAs based on the cognitive and motor function, and for those VTAs for which a score not meeting a predetermined threshold, the system may treat the VTA as one associated with a side effect. The system and method may visually indicate which explored VTAs are associated with side effects and which are not. Such graphics may be further considered by the clinician to ultimately make a final selection of the stimulation parameters to use.
  • It is noted that other factors may be used in selection of stimulation parameters, and, while the assessed cognitive and motor performance may be considered, the parameters resulting in the very best performance are not necessarily selected. Accordingly, parameters which result in a good performance, but not necessarily the best, may be selected.
  • In an example, a system user may select initial parameter settings by inputting a target VTA with minimal current creep to the non-motor regions and obtaining settings that provide an estimated VTA closely matching the target VTA. If the patient performs poorly on the administered tests, a new target VTA may be drawn with even less creep to the non-motor regions or at further distance from such regions, etc. As noted above, the cognitive and motor performance may be tested while visualizing the VTAs associated with particular parameters. The clinician can keep tweaking the target VTAs according to the test performance. That is, the clinician will be able to quickly see the results of the performance and those results relate to the position and size of the VTA.
  • Example embodiment of the present invention are directed to a computer system configured to provide a GUI via which the computer system may obtain user input according to which the computer system is configured to output a representation of a target VTA. The user input may be stimulation parameters and/or references to anatomical points, e.g., of a perimeter of the target VTA. The computer system may be configured to further provide a GUI via which the user may adjust parameters or points of the target VTA to obtain a desired target VTA. For example, the target VTA may be one that avoids non-motor anatomical regions to the extent described above. In an example embodiment of the present invention, the system may determine stimulation parameter settings that are estimated to provide a VTA that most closely matches the input target VTA. In an example embodiment, the system may operate under a condition that it limits the most closely matching estimated VTA to one that does not protrude beyond any point of the outer perimeter of the target VTA (even though there may be such a VTA that is a closer match to the target VTA).
  • For obtaining input for the generation of, and for generating, the target VTAs and/or for determining estimated VTAs, and/or for recording and visually outputting notes or indications of notes concerning cognitive and motor performance associated with VTAs, the system and method of the present invention may, for example, use processes described in U.S. patent application Ser. No. 12/454,330, filed May 15, 2009 and entitled “Clinician Programmer System and Method for Calculating Volumes of Activation” (“the '330 application”), in U.S. patent application Ser. No. 12/454,312, filed May 15, 2009 and entitled “Clinician Programmer System and Method for Calculating Volumes of Activation for Monopolar and Bipolar Electrode Configurations” (“the '312 application”), in U.S. patent application Ser. No. 12/454,340, filed May 15, 2009 and entitled “Clinician Programmer System and Method for Steering Volumes of Activation” (“the '340 application”), in U.S. patent application Ser. No. 12/454,343, filed May 15, 2009 and entitled “Clinician Programmer System Interface for Monitoring Patient Progress” (“the '343 application”), and in U.S. patent application Ser. No. 12/454,314, filed May 15, 2009 and entitled “Clinician Programmer System and Method for Generating Interface Models and Displays of Volumes of Activation” (“the '314 application”), the content of each of which is hereby incorporated herein by reference in its entirety.
  • Example embodiments of the present invention are directed to a computer system configured to monitor a patient performance during, and/or to record results of, the tests described above, the results of which may be used to select the stimulation parameters.
  • The computer system(s) may include one or more processors, which may be implemented using any conventional processing circuit and device or combination thereof, e.g., a Central Processing Unit (CPU) of a Personal Computer (PC) or other workstation processor, to execute code provided, e.g., on a hardware computer-readable medium including any conventional memory device, to perform any of the methods described herein, alone or in combination. The one or more processors may be embodied in a server or user terminal or combination thereof. The user terminal may be embodied, for example, a desktop, laptop, hand-held device, Personal Digital Assistant (PDA), television set-top Internet appliance, mobile telephone, smart phone, etc., or as a combination of one or more thereof. The memory device may include any conventional permanent and/or temporary memory circuits or combination thereof, a non-exhaustive list of which includes Random Access Memory (RAM), Read Only Memory (ROM), Compact Disks (CD), Digital Versatile Disk (DVD), and magnetic tape.
  • Example embodiments of the present invention are directed to one or more hardware computer-readable media, e.g., as described above, having stored thereon instructions executable by a processor to perform the methods described herein.
  • Example embodiments of the present invention are directed to a method, e.g., of a hardware component or machine, of transmitting instructions executable by a processor to perform the methods described herein.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a patient specific model of deep brain stimulation (DBS), where a stereotactic coordinate system was defined relative to the imaging data, microelectrode recording data were entered into the model (thalamic cells, yellow dots; subthalamic cells, green dots; substantia nigra cells, red dots), a three dimensional brain atlas was fitted to the neuroanatomy and neurophysiology (yellow volume, thalamus; green volume, subthalamic nucleus), and a DBS electrode was positioned in the model, pertaining to a theoretical ellipsoid target volume, and referring to data presented for patient No 1.
  • FIG. 2 shows a representative volume of tissue activated (VTA) for the Right and Left stimulators during Clinical and Model DBS settings referring to data presented for patient No. 1, where A) Right side Model settings: contact 2, 2.0V, 0.06 ms, 130 Hz, B) Left side Model settings: contact 3, 1.8 V, 0.06 ms, 130 Hz, and C) Right side Clinical settings: contact 2-3+, 4.0V, 0.06 ms, 130 Hz. D) Left side Clinical settings: contact 2, 3.2V, 0.06 ms, 130 Hz.
  • FIG. 3 illustrates working memory performance as percent of letters correctly repeated during single- and dual-task conditions, pertaining to (A) results of the n-back task in the single-task condition at Off DBS, Clinical DBS and Model DBS (Means and Standard Errors), and (B) results of the n-back task in the dual-task condition at Off DBS, Clinical DBS and Model DBS (Means and Standard Errors), and where a cross marks a significant differences between Off and Clinical DBS, an asterisk marks a significant difference between Off and Model DBS, and a double asterisk marks a significant difference between Clinical and Model DBS.
  • FIG. 4 shows representative force-tracking trials (pertaining to patient 1) during Single (left-most column) and all Dual-task conditions (right columns) under the three DBS settings: Off (upper plots), Clinical DBS (middle plots) and Model DBS (lower plots), where the horizontal line represents the target force line the patient was instructed to match.
  • FIG. 5 shows force-tracking performance across stimulation conditions, where (A) results of the time within the target range (TWR) of force in the Single and Dual-task conditions at Off DBS, Clinical DBS and Model DBS (Means and Standard Errors), and (B) results of the relative root mean square error (RRMSE) force in the single and dual-task conditions at Off DBS, Clinical DBS and Model DBS (mod DBS) (Means and Standard Errors), and where a cross marks a significant differences between Off and Clinical DBS, an asterisk marks a significant difference between Off and Model DBS, and a double asterisk marks a significant difference between Clinical and Model DBS.
  • FIG. 6 shows dual-task losses (DTLs) and standard errors for (a) the force maintenance task (TWR), and (b) RRMSE at Off DBS, Clinical DBS (cli DBS), and Model DBS (mod DBS), where an asterisk signifies DTLs significantly greater then zero and significant differences between the states of stimulation (*p<0.05).
  • FIG. 7 is a flowchart showing a stimulation parameter selection method, according to an example embodiment of the present invention.
  • DETAILED DESCRIPTION
  • Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for improving the cardinal motor signs of advanced Parkinson's disease (PD) (The Deep Brain Stimulation Study Group, “Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease,” N. Engl. J. Med. 345, 956-63 (2001), the entire contents of which is hereby incorporated by reference herein). Other target sites are effective for treating other motor, cognitive, and/or cognitive-motor disorders as outlined above. While bilateral STN DBS is considered safe, an emerging concern is the potential negative consequences it may have on cognitive functioning and overall quality of life (Freund, H. J., “Long-term effects of deep brain stimulation in Parkinson's disease,” Brain 128, 2222-3 (2005); Rodriguez-Oroz et al., 2005; Saint-Cyr, J. A. et al., “Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease,” Brain 123 (Pt 10), 2091-2108 (2000), the entire contents of each of which is hereby incorporated by reference herein). A recent report indicates patients' perceptions of their day-to-day function is improved subtly by DBS; however, caregivers perceived the patient as exhibiting subtle declines in day-to-day functioning (Duff-Canning, S. J. et al., “He said, she said: Differences between self and caregiver ratings of postoperative behavioral changes in Parkinson's disease patients undergoing bilateral subthalamic nucleus deep brain stimulation,” In: Twelfth International Congress of Parkinson's disease and Movement Disorders, vol. 23, ed.̂eds. Wiley-Blackwell, Chicago, Illinois, p. S127 (2008), the entire contents of which is hereby incorporated by reference herein).
  • Several long-term studies examining changes in cognitive function suggest that bilateral STN DBS results in varying levels of decline in overall cognitive functioning, including verbal fluency (Contarino, M. F. et al., “Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease,” J Neurol Neurosurg Psychiatry 78, 248-52 (2007); Funkiewiez, A. et al., “Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease,” J Neurol Neurosurg Psychiatry 75, 834-9 (2004), the contents of each of which is hereby incorporated by reference herein) and working memory (Rodriguez-Oroz et al., 2005; Schupbach, W. M. et al., “Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up,” J. Neurol. Neurosurg. Psychiatry 76, 1640-4 (2005) (hereinafter “Schupbach et al., 2005”), the entire contents of each of which is hereby incorporated by reference herein). Although some of these long term results may be due to natural progression of PD, they provide compelling evidence to suggest that bilateral STN DBS may adversely affect different features of cognitive functioning and bring into question earlier views that STN DBS does not impair cognition. For example, measures of verbal fluency and learning and memory, exhibited significant declines when comparing bilateral STN DBS to pre-surgery or OFF DBS scores (OFF typically referring to the temporary turn off of DBS for a research or clinical protocol) (Woods, S. P. et al., “Neuropsychological sequelae of subthalamic nucleus deep brain stimulation in Parkinson's disease: a critical review,” Neuropsychol. Rev. 12, 111-26 (2002), the entire contents of which is hereby incorporated by reference herein). In a meta-analysis that included data from 1,398 patients with bilateral STN DBS, cognitive problems were seen in 41 percent of patients (Temel, Y. et al., “Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: A systematic review,” Parkinsonism Relat. Disord. (2006), the entire contents of which is hereby incoporated by reference herein). Cognitive problems varied from a moderate deterioration in verbal memory to significant declines in executive functioning.
  • While cognitive declines are commonly seen with STN DBS, the degree of measured effect may be attributable to variation in the difficulty of the cognitive testing across studies Hershey, T. et al., “Stimulation of STN impairs aspects of cognitive control in PD,” Neurology 62, 1110-4 (2004), the entire contents of which is hereby incoporated by reference herein). The majority of studies examining the cognitive effects of STN DBS have utilized relatively simple neuropsychological tests suitable for use in a clinical environment. Therefore, reports of no or minimal effect of STN DBS on cognitive functioning may be explained by a lack of difficulty in test selection or the artificial environmental, free of distraction, in which they are completed. Hershey and colleagues (Hershey et al., 2004) reported that bilateral STN stimulation decreased working memory under cognitively demanding conditions. Those results are added to by examining cognitive and motor function individually and simultaneously under different levels of cognitive demands (Alberts et al., 2008). As working memory demands increased, cognitive, motor and cognitive-motor function decreased during bilateral compared to unilateral STN DBS (Alberts et al., 2008). Based on the inventors' results, it is believed that the spread of current to non-motor regions of each STN may be responsible for the disruption in cognitive, motor and cognitive-motor function during bilateral STN DBS.
  • Given its small size, stimulation within the STN, even with electrode contacts located predominately within the sensorimotor territory, can result in the spread of current to limbic and associative areas as well as to surrounding structures and fiber systems that may also affect cognition (Maks, C. B. et al., “Deep brain stimulation activation volumes and their association with neurophysiological mapping and therapeutic outcomes,” J. Neurol. Neurosurg. Psychiatry 80, 659-66 (2009), the entire contents of which is hereby incoporated by reference herein). The electric field generated by DBS is non-discriminately applied to all of the neural elements surrounding the electrode, and these stimulation effects are subsequently transmitted throughout the basal ganglia and thalamocortical networks (Asanuma, K. et al., “Network modulation in the treatment of Parkinson's disease,” Brain 129, 2667-78 (2006); Karimi, M. et al., “Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease,” Brain 131, 2710-9 (2008); Phillips, M. D. et al., “Parkinson disease: pattern of functional MR imaging activation during deep brain stimulation of subthalamic nucleus—initial experience,” Radiology 239, 209-16 (2006), the entire contents of each of which is hereby incoporated by reference herein). In turn, diminished cognitive function may be due to nonselective activation of non-motor pathways within and around the STN. However, according to the present invention, when the STN is stimulated, current spread to limbic and associative regions as well as throughout the basal ganglia and Thalamocortical networks is avoided through software modeling and calculations of those VTAs.
  • The interplay between the patient and clinician performing the DBS parameter selection is critical in defining the balance between therapeutic benefit and stimulation induced side effects. However, clinical DBS programming is typically done without the opportunity to visualize the spread of stimulation relative to the surrounding anatomy. In turn, current spread into non-target areas could occur without overt clinical signs, but still result in side effects not typically tested for in traditional clinical programming sessions. Therefore, recently developed Windows-based software tools that enable 3D visualization of the volume of tissue activated (VTA) by DBS as a function of the stimulation parameters and electrode location in the brain have been developed (Butson, C. R. et al., “StimExplorer: deep brain stimulation parameter selection software system,” Acta Neurochir Suppl. 97, 569-74 (2007) (hereinafter “Butson et al., 2007b”); Miocinovic et al., 2007, the entire contents of each of which is hereby incoporated by reference herein). In an example embodiment, quantitative theoretical predictions are used to define stimulation parameter settings, customized to the patient, maximizing stimulation of target areas and minimizing stimulation spread to non-target areas.
  • Described herein is a comparison of the effectiveness of two DBS programming strategies, standard Clinical (where current is spread throughout the dorsal and ventral portions of the STN) and Model-based, on cognitive-motor performance in advanced PD patients under dual-task conditions, where the primary criterion for the selection of Model DBS parameters is maximizing stimulation of target areas in the subthalamic region while minimizing stimulation of associative/limbic (ventral) sections of the STN. The target areas were defined as the dorsal STN and white matter dorsal to the STN (FIG. 1) (Butson, C. R. et al., “Patient-specific analysis of the volume of tissue activated during deep brain stimulation,” Neuroimage 34, 661-70 (2007) (hereinafter “Butson et al., 2007a”); Maks et al., 2009). Minimizing spread of current to the non-motor regions of the STN and focusing current spread to areas previously shown to produce ideal therapeutic benefit may minimize cognitive-motor declines under dual-task conditions without compromising improvements in motor function.
  • A total of 10 participants with advanced PD between the ages of 51 and 72 years (mean 58.6) participated in a study. Table 1 contains patient demographics and time since DBS surgery (DBS duration) and Table 2 contains Clinical and Model DBS parameters. All patients had undergone simultaneous bilateral STN DBS surgery at the Cleveland Clinic at least 14 months prior to study participation. Surgical procedures for DBS implantation have been reported in detail previously (Machado, A. et al., “Deep brain stimulation for Parkinson's disease: surgical technique and perioperative management,” Mov. Disord. 21 Suppl. 14, S247-58 (2006), the entire contents of which is hereby incorporated by reference herein). Stimulation parameters for DBS devices were clinically determined using the methods described by Moro and colleagues (Moro et al., 2006) and were stable for at least six months prior to study participation. The programming of stimulators was overseen by an experienced DBS programming team consisting of a programming nurse and movement disorders neurologist specializing in PD. Because participants needed to make verbal responses during the working memory test, patients with dysarthria or speech impairment were excluded. Prior to data collection, all participants signed an informed consent approved by the Cleveland Clinic Institutional Review Board.
  • TABLE 1 Patient demographics and UPDRS-III scores during Off, Clinical and Model DBS conditions and the percent change from Off to Clinical and Off to Model DBS. DBS UPDRS-III (%) duration UPDRS-III score Off to Off to Patient Gender Age (years) (months) Off Clinical Model Clinical Model 1 F 52 14 61 32 35 47.54 42.62 2 M 51 40 65 30 40 53.85 38.46 3 M 54 26 50 31 31 38.00 38.00 4 M 63 38 56 35 32 37.50 42.86 5 M 71 29 61 26 30 57.38 50.82 6 M 53 17 44 26 18 40.91 59.09 7 M 72 35 51 31 29 39.22 43.14 8 M 51 33 55 30 27 45.45 50.91 9 M 61 45 68 28 31 58.82 54.41 10  M 58 14 56 31 32 44.64 42.86 Mean 58.60 29.10 56.70 30.00 30.50 46.33 46.32 SD 7.55 10.55 6.90 2.61 5.35 7.53 6.70
  • A 6 degree of freedom force-torque transducer (Mini-40 Model, ATI Industrial Automation, Garner, N.C., USA) was used to measure normal force (Fz; grip) during a force-tracking motor task. Grip force was measured with a resolution of 0.06 N at a sampling rate of 128 Hz. A customized LabView program developed by the inventors' laboratory was used to collect and display force data to the participant. In an example embodiment of the present invention, stimulation parameters may be selected based on results of a force-maintenance task test (e.g., in combination with a cognitive function test), where the force-maintenance task test is performed using a 6 degree of freedom force-torque transducer to measure the force. Moreover, the described resolution of 0.06 N may be used at the sampling rate of 128 Hz.
  • The N-Back Task
  • Various forms of the n-back task have been used in a number of previous studies (for comprehensive review see Owen, A. M. et al., “N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies,” Hum. Brain Mapp. 25; 46-59 (2005), the entire contents of which is hereby incorporated by reference herein). The n-back task utilized in the current study was based on the methods originally used in its development. This version of the n-back task requires the participant to repeat the nth item back (e.g., 0-back, 1-back, 2-back) in a sequentially presented list of items (Dobbs, A. R. et al., “Adult age differences in working memory,” Psychol Aging 4, 500-3 (1989), the entire contents of which is hereby incorporated by reference herein). This same technique was used in a recent dual-task study with advanced PD patients during unilateral and bilateral STN DBS (Alberts et al., 2008). The difficulty level of the n-back task is manipulated by requiring the participants to remember items further back in the list. The type of n-back test used in this study utilized a list of random letters presented to the participant. The number of intervening letters varied from zero to two. This method of n-back testing requires encoding, maintenance, updating and output. However, unlike other versions of the task it does not require comparison or decision-making.
  • Two English-speaking experimenters administered the n-back task. Experimenter 1 read aloud the randomized letter sets of the n-back task while experimenter 2 monitored the participant's responses for accuracy. Participants were asked to respond by articulating the letter presented directly before (0-back), 1 cycle before (1-back), or two cycles before (2-back). If the participant provided an incorrect response or was unable to answer correctly within the allotted time (1.5 s) the trial would begin with a new sequence of letters. If the participant provides the correct answer, additional letters may be presented for the rest of the 30 second trial. Approximately 19-23 trials (letters) were presented during a 30 second block. After performing the n-back task for 30 seconds, participants rested for 15-45 seconds and then repeated the n-back task under the same level of difficulty (0, 1- or 2-back). Participants performed five 30 second blocks at each n-back condition (0, 1- and 2-back). These five blocks were collected sequentially and were randomized across participants. To account for practice effects, all participants completed three practice trials (30 seconds each) at each n-back level prior to data collection. Three trials have been shown to be sufficient to ensure task comprehension and stable performance for advanced PD patients (Alberts et al., 2008); all participants in the current study reported task comprehension and demonstrated stable performance. All practice and test blocks consisted of a unique list of randomized letters to prevent any memorization of letters. In an embodiment in which parameters are selected on a per-patient basis based on how the patient performs during the described tests, the n-back test may be administered and parameter selection may be based on number of total errors during 30 seconds, number of correct responses, and number of letters before the first error.
  • Force-Maintenance Task
  • Participants used a precision grip (i.e., thumb and index finger only) of their dominant hand to exert an isometric force against the force transducer. Similarly, in an example embodiment of the present invention, a precision grip may be used in a force maintenance test, based on results of which stimulation parameters are selected. The participant's dominant band was determined using the Edinburg Handedness Inventory (Oldfield, R. C., “The assessment and analysis of handedness: the Edinburgh inventory,” Neuropsychologia. 9, 97-113 (1971), the entire contents of each of whichis hereby incoporated by reference herein). The force transducer was oriented in a comfortable position to the patient and affixed to the table to prevent any movement and for consistency throughout force tracking. Three maximum precision grip efforts, 5 seconds each, were completed at each of the three data collection sessions. These data were used to establish the maximum grip force of the patient. Between each maximum effort, patients rested 1-2 minutes. The peak force achieved from the three efforts was considered the maximum and was used to calculate a target force level; 20% of the maximum force. A target force level may similarly be selected for administering a test based on which to select stimulation parameters for a patient who performs the test. The 20% target force level was selected as Galganski and colleagues (Galganski, M. E. et al., “Reduced control of motor output in a human hand muscle of elderly subjects during submaximal contractions,” J. Neurophysiol. 69, 2108-2115 (1993), the entire contents of which is hereby incorporated by reference herein) found no differences in younger adults' and older adults' standard deviation (SD) at this force level and based on previous studies with younger adults, older adults and advanced PD patients this force level could be maintained relatively easily with minimal fatigue (Alberts et al., 2008; Voelcker-Rehage, C., Alberts, J. L., “Age-related difference in working memory and force control under dual-task conditions,” Aging, Neuropsychology, and Cognition 13, 1-19 (2006) (hereinafter “Voelcker-Rehage and Alberts, 2006”); Voelcker-Rehage, C. et al., “Effect of motor practice on dual-task performance in older adults,” J. Gerontol B Psychol. Sci. Soc. Sci. 62, P141-8 (2007) (hereinafter “Voelcker-Rehage and Alberts, 2007”), the entire contents of each of which is hereby incorporated by reference herein). The target force level produced and actual real-time grip force produced by the participant was displayed on a 21″ LCD monitor located ˜44-59 cm directly in front of the participant. Participants were instructed to match their grip force to the target force line as accurately as possible. An auditory stimulus “ready, go” signaled the participants to start matching their force to the target force. Participants performed one to five practice repetitions prior to test blocks to be certain all task requirements were understood. Ten force-maintenance blocks for each limb, 30 seconds each, were performed with at least 30 seconds of rest between each block. The test administered to a patient for determining stimulation parameters for the patient, according to example embodiments of the present invention, may be similarly administered.
  • Dual Task: N-Back and Force Maintenance Simultaneoulsy
  • Participants performed 15 dual-task blocks in which they were asked to simultaneously perform the n-back task and force maintenance task. The force maintenance task was performed in random combination with each of the three n-back conditions (0-back, 1-back, 2-back; five repetitions each). Participants were instructed to perform both tasks as accurately as possible and to devote half of their attention to the cognitive task and half of their attention to the motor task. Participants were given at least 30 seconds of rest between each block. The tests for selection of stimulation parameters on a per patient basis may be similarly administered.
  • Selection of Model DBS Parameters
  • For each subject enrolled in the study a patient-specific DBS computer model of each side of the patient's brain using Cicerone v1.2, a freely available academic DBS research tool (Miocinovic et al., 2007) (FIG. 1) was created. The models were created without any a priori knowledge of the patient, aside from access to their clinical MRI and CT imaging data, surgical targeting data, and intra-operative microelectrode recording (MER) data. Researchers were blinded to each patient's clinical symptoms, drug regiment, clinical DBS programming notes, and Clinical stimulation parameter settings.
  • Each patient-specific DBS model included coupled integration of MRI/CT data, MER data, 3D brain atlas surfaces, DBS electrodes, and VTA predictions all co-registered into the neurosurgical stereotactic coordinate system following previously described methodology (FIG. 1) (Butson et al., 2007a; Butson et al., 2007b; Miocinovic et al., 2007, all of which are incorporated by reference herein). The first phase of model development was to import imaging data into the software. The stereotactic coordinate system was defined by identifying fiducial landmarks of the neurosurgical head frame used to implant the electrode (FIG. 1A). The CT or MRI acquired with the frame in place was called the frame image and any subsequent imaging data used in the model was co-registered to the frame image. Co-registration between the frame image and an alternative image was performed manually within Cicerone using a two step process. First, coordinates of the anterior and posterior commissures (AC/PC), defined by the operating neurosurgeon, were used to initially register the two images together. Second, a nine panel graphical user interface (GUI) allowed for manual manipulation to fine tune the image fusion. This GUI displayed the axial, coronal, and saggital views of the frame image on the left column, the alternative image on the right column and an overlay of the two in the middle column. Because the images were from the same individual a rigid body transformation could be performed to bring the images into near perfect alignment.
  • The second phase of model development consisted of entering the stereotactic location of each MER data point, color coded based on its neurophysiologically defined nucleus, into the model (FIG. 1B,C). 3D anatomical representations of the various nuclei of interest (thalamus, subthalamic nucleus, etc.) were then scaled and positioned within the context of the pre-operative MRI and MER data (FIG. 1B,C). This process was performed manually, taking into account both anatomical structures visible in the MRI and fitting MER points within their respective nuclei, to provide the best possible overall fit of the brain atlas to the patient (Lujan, J. L. et al., “Automated 3-Dimensional Brain Atlas Fitting to Microelectrode Recordings from Deep Brain Stimulation Surgeries,” Stereotact. Funct. Neurosurg. 87, 229-240 (2009); Maks et al., 2009). Once the patient's anatomical model was defined, the electrode type (Medtronic Electrode Model 3387 or 3389) was selected and the implantation position of the DBS electrode, as defined by intra-operative stereotactic coordinates, was displayed within the model system (FIG. 1D). Comparison with the post-operative CT verified that the intended surgical placement of the DBS electrode was within the artifact of the imaged electrode.
  • Based on previous experience developing patient-specific models of therapeutic STN DBS (Butson et al., 2007a; Maks et al., 2009), a theoretical ellipsoid target volume (FIG. 1E) was defined. Stimulation of this target area, which included the dorsal STN and white matter dorsal to the STN, has been associated with excellent clinical outcomes in previous work. A stimulation parameter setting was defined for each side of each patient's brain that maximized stimulation coverage of the target volume and minimized stimulation spread outside of the target volume. This theoretically optimal parameter setting was called the “Model DBS” and it was defined using theoretical predictions of the volume of tissue activated (VTA) (FIG. 2). The VTA provides an electrical prediction of the volume of axonal tissue directly activated by DBS for a given stimulation parameter setting. The VTAs used in Cicerone v1.2 are pre-compiled solutions from the DBS models previously described. (Butson, C. R. et al., “Predicting the effects of deep brain stimulation with diffusion tensor based electric field models,” Medical Image Computing and Computer Assisted Intervention, International Conference on Medical Image Computing and Computer Assisted Intervention 9, 429-37 (2006) (hereinafter “Butson et al., 2006”), the entire contents of which is hereby incoporated by reference). The software provided the ability to quickly and interactively evaluate a wide range of stimulation parameter settings and enable definition of a theoretically optimal Model DBS for each side of each patient (Table 2).
  • TABLE 2 Clinical and model stimulation parameters for all patients Clinical Settings Model Settings Pulse Pulse Voltage Width Frequency Voltage Width Frequency Patient Contact (V) (μs) (Hz) Contact (V) (μs) (Hz) Left Stimulation Parameters 1 2-C+ 3.2 90 130 3-C+ 1.8 60 130 2 2-C+ 3.2 90 185 2-C+ 2.6 60 130 3 2-3+ 3.5 60 135 2-C+ 2.3 60 130 4 2-3+ 3.6 60 135 2-C+ 1.8 60 130 5 2-3+ 3.6 90 135 2-C+ 2.6 60 130 6 2-C+ 3.0 60 130 2-C+ 2.4 60 130 7 1-3+ 3.6 90 185 2-C+ 2.5 60 130 8 1-C+ 3.2 90 135 2-C+ 2.4 60 130 9 1-2-C+ 2.9 60 130 2-C+ 1.8 60 130 10 1-C+ 3.2 60 185 2-C+ 2.4 60 130 Right Stimulation Parameters 1 2-3+ 4.0 90 130 2-C+ 2.0 60 130 2 1-C+ 3.6 60 185 2-C+ 2.2 60 130 3 1-2+ 3.5 60 135 2-C+ 2.6 60 130 4 1-3+ 3.3 60 135 2-C+ 2.8 60 130 5 2-3+ 3.9 90 135 2-C+ 2.8 60 130 6 2-C+ 3.2 60 130 2-C+ 2.6 60 130 7 2-C+ 3.6 90 185 3-C+ 1.5 60 130 8 2-C+ 3.2 60 135 2-C+ 1.8 60 130 9 1-2-C+ 2.9 60 130 2-C+ 2.4 60 130 10 2-C+ 3.2 60 185 2-C+ 2.0 60 130
  • Following completion of the clinical study, the VTAs for each patient were quantified under both the Model and Clinical settings, along with their respective overlap with the STN volume. Each STN volume, as fitted to each hemisphere of each patient, was divided into a ventral and dorsal section. The STN division was defined by a plane parallel to the AC/PC plane that cut through the centroid of the STN. Table 3 contains the total VTA for each DBS condition and the percent in the ventral and dorsal portions of the STN (remaining numbers being outside the dorsal and ventral portions).
  • TABLE 3 Total volume of tissue activated (VTA) during Model and Clinical DBS and the percent of VTA within the dorsal and ventral portions of the STN for Model and Clinical settings. Model Clinical total total Patient Side VTA dorsal ventral VTA dorsal ventral 1 Left 45 13.8 0 116.6 47.4 18.9 1 Right 55.1 36.2 0.5 39 23.9 0 2 Left 71.7 20.3 0 108.9 31 0.6 2 Right 57.2 6.8 0 124.9 34.8 36.2 3 Left 65.4 28.2 2.3 29.1 12.3 0 3 Right 76.3 24.3 0.4 39.6 10.7 8.7 4 Left 49.6 25.7 0.3 29.8 15 0 4 Right 83.8 46.2 3.7 44.9 22.4 12.4 5 Left 76.4 38.9 6.4 33.6 19.5 0.2 5 Right 84.1 45.2 2.4 37.4 20.5 0 6 Left 68.4 22.1 0 96.9 32.3 0 6 Right 73.7 27.4 0.4 106.3 37.2 2.3 7 Left 68.9 13 0 45.3 4.2 6.3 7 Right 35.4 25.3 3.3 137.2 35.7 35.7 8 Left 68.2 17.5 0 129.1 28.2 28.5 8 Right 49.5 25.5 1.7 103.7 41.3 9.5 9 Left 47.4 12 0 199.9 78.8 33 9 Right 65.5 25.8 0 199.9 68.6 43.6 10  Left 64.5 21 0 106.3 39.5 37.7 10  Right 52.9 13 0 96.3 25.4 0 AVERAGE 63.0 24.4 1.1 91.2 31.4 13.7 STDEV 13.4 10.8 1.7 53.0 18.3 15.9 VTA (mm{circumflex over ( )}3)
  • Calculation of Power Requirements for Stimulation Parameters
  • Waveforms were simulated according to the specific output of the Medtronic implanted pulse generator (Butson, C. R. et al., “Differences among implanted pulse generator waveforms cause variations in the neural response to deep brain stimulation,” Clin Neurophysiol. 118, 1889-94 (2007) (hereinafter “Butson and McIntyre, 2007”), the entire contents of which is hereby incorporated by reference herein). The power of stimulation with a given frequency, pulse width, and amplitude was calculated by averaging the instantaneous power over a 1 second period,
  • P ta = 1 T 0 T V ( t ) 2 R · t ,
  • where Pta is the time-averaged power, T is set to I s, V(t) is the instantaneous voltage, R input resistance, and t is time. The power consumption, in microwatts, was calculated for Clinical and Model DBS settings.
  • Procedure
  • All data were collected during two visits to a research laboratory at the Cleveland Clinic. These two data collection sessions were separated by at least 72 hours. For both sessions, participants reported to the laboratory in the clinically defined off condition (i.e., at least 12 hours since their last dose of antiparkinsonian medication) while on DBS with their clinically defined stimulation parameters. After completing the informed consent process, patients were evaluated clinically with the Unified Parkinson's Disease Rating Scale (UPDRS) Part-III Motor Exam administered by an experienced movement disorders neurologist. The same neurologist completed all ratings except for one experimental session (patient 9; Clinical settings).
  • Each participant completed evaluation and testing under three DBS conditions: Off DBS, Clinical DBS, and Model DBS across the two laboratory visits. The order of testing Clinical and Model DBS parameters were randomized across patients across the two laboratory visits. For example, Day 1 testing consisted of completing all tests while on Clinical DBS and then following completion the patient's stimulator was turned Off for three hours and all clinical, motor, cognitive and cognitive-motor testing was repeated. On Day 2 the patient would complete all testing using the Model DBS parameters. Five patients were tested under Clinical DBS on Day 1 and five patients completed Model DBS on Day 1. Within each experimental session, the single task conditions were completed before the dual-task conditions. The single task conditions were the n-back task (three levels of difficulty: 0- 1- and 2-back) and force maintenance task only. The order of completing the single task cognitive and motor tasks was randomized across patients. The order of dual-task conditions, force maintenance with the three different levels of n-back, was randomized across patients.
  • According to the embodiment where stimulation parameters are selected on a patient-specific basis based on results of such tests, the tests may be performed initially under the stimulation settings of the predicted model parameters as discussed above. Subsequently, the tests may be performed under parameters selected based on the clinician's judgment in view of the patient's performance on prior iterations of test administration and VTA size and shape for various settings. Additionally, the tests may be administered and data may be collected prior to programming when the patient has yet to have any stimulation, to obtain a baseline of cognitive-motor function.
  • The Clinical DBS and Off DBS experimental session patients completed all testing on two occasions within the same day: first under Clinical DBS parameters and then while Off DBS. After completing all clinical, cognitive, motor and cognitive-motor tests under Clinical DBS, the patient's stimulators were turned Off for three hours to allow the effects of DBS to wear off (Alberts, J. L. et al., “Comparison of pallidal and subthalamic stimulation on force control in patient's with Parkinson's disease,” Motor Control. 8, 484-99 (2004) (hereinafter “Alberts et al., 2004”); Alberts et al., 2008; Temperli, P. et al., “How do parkinsonian signs return after discontinuation of subthalamic DBS?,” Neurolog. 60, 78-81 (2003), the entire contents of each of which is hereby incorporated by reference herein). During this three hour wash out period the patient remained in the laboratory and was provided lunch and rested. Following the 3 hour wash out period, the patient repeated all clinical, cognitive, motor and cognitive-motor tests. Upon completion of this experimental session, the patient's stimulators were turned on (Clinical DBS parameters were restored) and they resumed their antiparkinsonian medication. Approximately 30 minutes after taking their medication and restoration of DBS the patient departed the laboratory. The total time spent in the laboratory during a Clinical DBS and Off DBS experimental session was approximately 5-6 hours (˜2 hours of data collection and 3 hours rest during the wash out period).
  • The Model DBS experimental session, which randomly occurred on Day 1 or Day 2, was completed in approximately 4-5 hours. For the Model DBS session, the patients arrived in the laboratory off antiparkinsonian medication and on Clinical DBS. Upon arrival, both stimulators were turned Off. The patient then rested in the laboratory for the next two hours. After two hours the patient was re-programmed using the Model DBS parameters. After 60 minutes under Model DBS parameters, the patient completed all clinical, cognitive, motor and cognitive-motor testing. Upon completion of the Model DBS testing session, the patient's stimulators were reprogrammed to their clinically defined parameters and they took their anti-parkinsonian medication and departed the lab approximately 30 minutes later.
  • Data Analysis
  • Force-maintenance: All force data were filtered with a phase-symmetric low-pass filter employing Woltring's algorithm (detailed in previous studies (Voelcker-Rehage, C., Stronge, A. J. et al., “Age-related differences in working memory and force control under dual-task conditions,” Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 13, 366-84 (2006) (hereinafter “Voelcker-Rehage et al., 2006”); Voelcker-Rehage and Alberts, 2007)) using existing Matlab analysis programs developed in the inventors' laboratory. Force data were assessed to determine the patients' accuracy from three seconds after the start of the block until completion of the block; this period allowed the patient sufficient time to achieve the target force. That is, test results were collected beginning after three seconds. The primary motor outcome variables for the force-tracking task were time within the target range (TWR) and relative root mean square error (RRMSE). The TWR is calculated by determining the time the patient's force trace is within ±2.5% of the target line, i.e. within 2.5% of the force, such that, for example, if the target force is 5N, the TWR is the time at which a force is maintained in the range of 4.375-5.625N. This may be different for each patient, based on the patient's target force. The assessment was done after the data collection so the patient was not targeting this region specifically. The TWR provides an overall accuracy measure of force-tracking. To account for differences in the amplitude of the target force (e.g., inter-patient and intra-patient variability due to stimulation status), the RRMSE, as defined in equation 1, was used as a method of normalizing performance relative to force amplitude. The RRMSE is considered to reflect the overall variability of force-tracking performance; a lower RRMSE suggests control of distal musculature and hand functionality (Kriz, G. et al., “Feedback-based training of grip force control in patients with brain damage,” Arch. Phys. Med. Rehabil. 76, 653-659 (1995); Kurillo, G. et al., “Force tracking system for the assessment of grip force control in patients with neuromuscular diseases,” Clin. Biomech (Bristol, Avon) 19, 1014-21 (2004), the entire contents of each of which is hereby incorporated by reference herein). In the equation below, FT(t) is the target force provided to the patient, F0(t) is the force produced by the patient and T is the time of the block.
  • R R M S E = 1 T t = 0 T ( F 0 ( t ) - F T ( t ) ) 2 max ( F T ) 2
  • TWR and RRMSE may be used according to the embodiment where test results are used for selection of parameters on a patient specific basis. Greater TWR reflects better performance and lower RRMSE reflects better performance.
  • N-back performance: N-back performance was measured by determining the percentage of correct letters recalled during a 30 second block and the total number of errors committed during a block (Voelcker-Rehage et al., 2006).
  • Dual-task Analysis: To examine participants' performance under the dual-task conditions, the dual task loss (DTL) was computed using a standard measure to compare performance on single and dual-task conditions (Lindenberger, U. et al., “Memorizing while walking: increase in dual-task costs from young adulthood to old age,” Psychol. Aging 15, 417-436 (2000), the entire contents of which is hereby incorporated by reference herein). The DTLs were computed as the percentage of loss in motor and cognitive performance during dual-task conditions relative to performance in the single-task conditions in the following manner:

  • DTLforce=[(mean dual-taskforce−mean baselineforce)/mean baselineforce]×100.

  • DTLn-back=[(mean dualn-task−mean baselinen-back)/mean baselinen-back]×100.
  • This is a measure that essentially determines the cost from a motor and cognitive perspective of moving from a single task to the more complex and difficult dual-task.
  • Statistical Analysis
  • Motor (RRMSE, TWR) and cognitive (percentage of correctly repeated letters (PRL), number of errors (NE)) performance data were analyzed with repeated measures ANOVAs (analysis of variance). Greenhouse Geyser adjustment was reported when the sphericity assumption was violated. Post-hoc contrasts (Bonferroni adjustment) were used to determine differences between the DBS status and level of task difficulty to determine the conditions that were most affected by the different DBS parameter settings. Analyses were conducted separately for the motor and cognitive task. These statistical methods may be applied according to the embodiment in which parameters are selected based on the test results.
  • Two 3 (DBS condition: Off DBS, Clinical DBS, Model DBS)×3 (task difficulty: 0-back, 1-back, 2-back)×2 (context: single-task, dual-task) repeated measure ANOVAs were used to determine differences between different DBS parameter settings in n-back difficulty and between single- and dual-task context using PRL and NE. The repeated measure ANOVAs may be used when the study design is a within subject repeated measure, such that multiple measures on the same patient are obtained, but under varying conditions. Additionally, two 3 (DBS condition)×4 (task difficulty: force only, force at 0-back, 1-back, and 2-back difficulty) repeated measure ANOVAs were carried out using the RRMSE and TWR scores.
  • To examine whether DTLs for the force maintenance task and the n-back difficulties were significantly different from zero, a series of one-sample t tests (test value=0) were conducted separately for each DBS condition. Repeated measures ANOVAS with corresponding post-hoc tests were used to compare the DTLs for task difficulties (0-back, 1-back, 2-back) and DBS status. If there is no cost in moving from a single to a dual task, then the DTL would be zero.
  • Results
  • Clinical Ratings
  • Table 1 contains UPDRS-III Motor scores for each patient during Off, Clinical, and Model DBS. For all patients, the UPDRS-III scores decreased (and lower is better) with Clinical and Model DBS compared to Off DBS. Clinical DBS, on average, resulted in a 46 percent improvement in UPDRS-III ratings (range: 37 to 58 percent) while Model DBS also improved clinical UPDRS-III ratings by 46 percent (range: 38 to 59 percent). Statistical analysis (t-tests for paired samples) revealed that UPDRS-III scores for Clinical and Model DBS were significantly better than Off DBS (tcli-off(9)=3.90, p=0.004; tmod-off(9)=3.30, p=0.009). However, there was no statistical difference in UPDRS-III scores between Clinical and Model DBS settings (t(9)=0.23, p=0.820).
  • DBS Power Consumption
  • The power consumption associated with Clinical and Model parameters for each stimulator and the total amount of power, in microwatts, is provided in Table 4. In terms of total power consumption, the Model parameters consume approximately 50 percent less microwatts than Clinical parameters (tmod-cli(9)=8.45, p<0.0001). For all 10 patients, total power consumption was less with Model compared to Clinical parameters and power consumption was less with Model compared to Clinical parameters for both the right and left stimulators.
  • TABLE 4 Power consumption, in microwatts, for Clinical and Model stimulation parameters for each side and total power requirements for Clinical and Model parameters. Power (μW) Clinical Model Total Patient Left Right Left Right Clinical Model 1 122.65 191.63 25.67 31.69 314.28 57.36 2 174.53 146.13 53.56 38.35 320.66 91.91 3 100.79 100.79 41.91 53.56 201.58 95.47 4 106.63 89.60 25.67 62.12 196.24 87.79 5 161.19 189.18 53.56 62.12 350.37 115.68 6 71.31 81.13 45.64 53.56 152.44 99.20 7 220.89 220.89 49.52 17.83 441.79 67.35 8 127.36 84.25 25.67 45.64 211.62 71.31 9 66.63 66.63 25.67 45.64 133.27 71.31 10  115.46 115.46 45.64 31.69 230.92 77.33 Mean 126.75 128.57 39.25 44.22 255.32 83.47 SD 47.43 54.77 12.21 14.39 97.70 17.62
  • Cognitive Functioning and DBS During Single and Dual-Task Conditions
  • Percentage of Correct Letters (PCL): The results from the repeated measures ANOVA (cf. FIG. 3) revealed that overall n-back performance decreased with increasing task difficulty (F(2, 18)=48.422, p<0.001, η2=0.843). The main effects of DBS status (F(2, 18)=2.010, p=0.163) did not achieve statistical significance while the main effect of context (F(2, 18)=4.879, p=0.055) approached statistical significance. The task difficulty×DBS condition interaction, however, was significant (F(4,18)=2.945, p=0.033, η2=0.247), resulting from a greater performance decrease with increasing n-back difficulty for Clinical DBS than for Off and Model DBS. Performance on the 2-back during Clinical DBS was significantly lower than performance at Off DBS or Model DBS in single-task conditions. As task difficulty increases as a result of an increase in cognitive demands of the dual-task performance, declines would be found during Clinical DBS, but not during Model DBS.
  • Number of Errors (NE): Errors in cognitive function were primarily due to responding with the incorrect letter and the participant reporting to experimenter that they did not remember the letter to be recalled. Less than 0.5 percent of the errors were the result of the patient not responding within the ˜1.5 second time period. For the number of errors, the effect of task difficulty (F(2, 18)=50.381, p<0.001, η2=0.848) and the task difficulty by context interaction (F(2, 18)=3.859, p=0.040, η2=0.300) were significant. Participants produced more errors as the difficulty of the n-back task increased. The number of errors, however, did not significantly differ between the DBS states (F(2, 18)=0.450, p=0.644). This can occur, for example, as a function of the number of letters presented. For example someone can perseverate on a response and not get as many letters presented to that person.
  • Motor Function and DBS During Single and Dual-Task Conditions
  • Representative force-tracking data for an entire set from one patient for all three DBS conditions during single and dual-task settings are presented in FIG. 4. When performing the force-tracking task only (left plots), Clinical and Model DBS resulted in better tracking performance compared to Off DBS.
  • While patients were Off, force tracking performance became slightly more variable as the difficulty of the dual-task increased. During Clinical DBS, middle plots, force-tracking performance declined dramatically as task difficulty increased, in particular during the 2-back condition in which variability was greatest. The lower panels depict force-tracking trials during Model DBS. In general, the consistency of force tracking was relatively unaffected by increasing task difficulty under dual-task conditions. The TWR and RRMSE measures were used to quantify force-tracking performance.
  • Time within Target Range (TWR): When completing the force maintenance task only, Clinical and Model DBS conditions were significantly better than the Off DBS condition. As expected, motor performance tended to decrease (lower TWR) as patients moved from the single to dual-task conditions (cf FIG. 5 a). However, the rate of decline in motor performance differed across stimulation conditions. With Clinical DBS the rate of motor performance decline was greater compared to the decline under Model DBS settings. A significant interaction between DBS condition and task difficulty was present (F(6,54)=4.857, p<0.001, η2=0.351). During Off and Model DBS conditions, the slope of decline in motor performance was similar across dual-task conditions. However, under Clinical DBS settings, TWR decreased dramatically across all task difficulties. Furthermore, Model DBS led to significantly better force tracking performance as compared to Clinical DBS or Off DBS in all dual-task conditions.
  • Relative root mean square error (RRMSE): In general, the variability in force tracking increased significantly as task difficulty increased, moving from single to dual-task conditions (F(1.35,27.73)=10.113, p=0.005, η2=0.529). Additionally, the force variability differed between the three DBS conditions (F(2,54)=5.042, p=0.018, η2=0.359), and the greatest variability occurred under Clinical DBS. In the dual-task conditions, Clinical DBS resulted in significantly worse performance than Off and Model DBS (cf. FIG. 5 b). As shown in FIG. 5 b, Clinical DBS resulted in more variable force production across conditions; as task difficulty increased to the 2-back condition, force variability was significantly greater compared to Model DBS.
  • Dual-task losses (DTLs) different from zero: The DTLs for n-back performance at the 0-back condition were relatively small and non-significant across the three DBS testing conditions. Declines in n-back performance were greater when moving from the single task 1-back condition to the dual-task 1-back condition, in particular for the Off DBS and Model DBS conditions (due to the fact that under single task conditions n-back performance was relatively high). In study data, the DTLs associated with Clinical DBS were not significantly different from the DTLs associated with Model DBS. From a cognitive perspective, the cost in performance when moving from single- to dual-task conditions was not statistically significant for any of the stimulation conditions. A reason for this may be that, despite the fact that patients reported attending to both tasks equally, they may have placed greater emphasis or allocated more attentional resources to performing the working memory task compared to force-tracking.
  • As expected, force tracking performance did decline as task complexity increased from single to dual-task conditions while Off DBS and under Clinical and Model DBS settings. However, the declines in force tracking, FIGS. 6 a and 6 b, were most present during Clinical DBS settings. For TWR, the greatest declines in motor performance when moving from a single to dual-task were associated with Clinical DBS (Clinical DBS: t0-back(9)=3.091, p=0.013; t1-back(9)=3.058, p=0.014; t2-back(9)=7.151, p<0.001; Model DBS: t0-back(9)=0.537, p=0.604; t1-back(9)=0.771, p=0.460; t2-back(9)=2.363, p=0.042; Off DBS: t0-back(9)=−1.542, p=0.157; t1-back(9)=0.269, p=0.794; t2-back(9)=2.026, p=0.073). The greatest performance decrements for each DBS condition occurred during the most complex testing condition, 2-back+force maintenance (compared to just force maintenance without the n-back test), and the smallest decrement during the simplest, 0-back+force maintenance (cf. FIG. 6 a) (compared to just force maintenance without the n-back test). That is, as complexity of the task is increased, the quality of performance decreases, A similar pattern of results was present when examining the variability of force production (RRMSE): t0-back(7)=3.54, p=0.01; t1-back(7)=3.33, p=0.01; t2-back(7)=7.42, p<0.01) (cf. FIG. 5 b). The greatest declines in motor performance were associated with Clinical DBS (t0-back(9)=−1.674, p=0.128; tt-back(9)=−2.636, p=0.027; t2-back(9)=−2.970, p=0.016). The DTLs in force tracking performance (RRMSE) at Off DBS were significant for all n-back conditions (t0-back(9)=−3.767, p=0.004; t1-back(9)=−5.023, p=0.001; t2-back(9)=−4.131, p=0.003), whereas under Model DBS DTLs were not significant (t0-back(9)=−2.014, p=0.075; t1-back(9)=−2.005, p=0.076; t2-back(9)=−1.924, p=0.087).
  • Task difficulty and Stimulation differences in DTLs: The DTLsn-back, in general, increased significantly as task difficulty also increased, (F(2, 18)=3.831, p=0.041, η2=0.299). However, the DTLsn-back were not differentially affected across stimulation conditions (Off, Clinical or Model) (F(2, 18)=0.425, p=0.660).
  • For the DTLsforce, a significant main effect of task difficulty for TWR was present (F(2, 18)=26.984, p<0.001, η2=0.750). As task difficulty increased, DTLs in force maintenance also increased as shown in FIG. 6 a. The loss in motor performance was relatively small for the 0-back condition while relatively large for the 2-back dual-task condition. A significant main effect of stimulation (F(2, 18)=5.940, p=0.010, η2=0.398) was present. Differences between DBS states were significant in the 0-back, 1-back and 2-back conditions (significantly higher DTLs with Clinical DBS compared to Off and Model DBS). The DTLs in terms of the variability (RRMSE) of force production were similar to TWR as losses in performance were greater during Clinical compared to Off and Model DBS conditions (FIG. 6 b).
  • Discussion
  • Recently, it has been shown that bilateral STN DBS disrupts PD patients' cognitive-motor functioning under dual-task conditions (Alberts et al., 2008). These DBS related declines in cognitive-motor functioning are minimized through the use of patient-specific DBS models that account for electrode location and the VTA. In an example embodiment, the primary criterion for the selection of DBS parameters may be maximized stimulation coverage of a target volume that includes the dorsal STN and white matter dorsal to the STN, thus minimizing stimulation of non-motor regions of the STN.
  • The typical clinical method of DBS programming was compared, with respect to cognitive-motor performance in advanced PD patients, to the computational approach described herein for selecting DBS parameters that minimize stimulation of non-motor regions of the STN. Clinical assessments indicated both methods of DBS programming were effective in improving UPDRS-III scores. However, under all dual-task conditions motor performance was, in general, better with Model determined stimulation parameters compared to Clinical settings. In addition, cognitive performance (working memory) was better during modestly complex task conditions, using Model compared to Clinical settings. Overall, these data suggest that cognitive-motor declines associated with bilateral STN DBS can be mitigated through the use of software that depicts the VTA associated with a given parameter setting relative to the targeted brain structure.
  • Referring to FIG. 7, in an example embodiment of the present invention, a system may, at step 700, output a GUI including a display of a model of a patient anatomy, e.g., the patient's brain, co-registered with a model of a stimulation leadwire. The brain model may be generated, for example, by fitting a brain atlas to images of the patient's brain. Alternatively, the images themselves may be displayed. Alternatively, the system may display the images and the model co-registered with each other.
  • At step 702, the system may obtain user input identifying a target VTA. The target VTA may be drawn such that it does not include more than 10% of the non-motor region of the patient brain, and specifically less than 10% of globus pallidus. In an example, the target VTA may be drawn such that it does not include any of the non-motor region.
  • At step 704, the system and method may determine an estimated VTA and corresponding stimulation parameters whose stimulation is estimated to produce the estimated VTA, which estimated VTA most closely matches the obtained target VTA. In an example embodiment, the estimated VTAs (and corresponding stimulation parameters) from which the system may select may be limited to those that do not extend outward beyond any of the perimeter of the target VTA, such that if the closest estimated VTA extends beyond the target VTA, a VTA that is less of a match but is completely included within the area of the target VTA would be selected. The estimated VTAs may be calculated based on predetermined functions and/or based on a patient population as further described in the '330, '312, '340, '343, and '314 applications.
  • In an alternative example embodiment, the system may be initially configured with a universal target VTA drawn to the generic model which is then mapped to the specific patient, separate input of a target VTA for each patient not being necessary. The system may provide a patient-specific closest matching estimated VTA and associated stimulation parameters based on the universal target VTA as applied to the patient model and based on a currently used electrode leadwire.
  • The clinician may use the output parameters for bilateral DBS stimulation for the patient. Because the parameters correspond to an estimated VTA that closely matches the target VTA which does not include stimulation of non-motor regions, or at least only up to 10% of such regions of the brain, and specifically less than 10% of globus pallidus, there would be significant improvement with respect to cognitive and/or motor-cognitive degeneration as compared to conventional bilateral DBS stimulation.
  • At step 706, the system and method may display the estimated VTA overlaid on the patient brain/leadwire model. For example the system may remove the target VTA from display, the estimated VTA being displayed in its place.
  • In an example embodiment of the present invention, cognitive, motor, and cognitive-motor function of the patient may be assessed to fine tune the stimulation parameters. For example, at step 708, the stimulation parameters corresponding to the estimated VTA may be used in a stimulation of the patient brain. Instead of the stimulation parameters corresponding to the estimated VTA, the system may allow for the clinician to provide input to modify the stimulation parameters, e.g., directly or by shifting the displayed estimated VTA or a displayed current field.
  • While the patient undergoes such stimulation, motor and cognitive tests, e.g., the combination of the n-Back test and the force-maintenance task as described above, may be administered. The system, at step 710, may record results of such tests. For example, the system may record and/or calculate the data corresponding to the graphs shown in FIGS. 3-6. With respect to force-maintenance, the system may include a force sensor that senses the force exerted by the patient, and may record such figures and determine the difference of such sensed force to a target force. The system may also output audio through a speaker listing a series of letters and may receive speech input via a microphone repeating letters for the n-back test. The system may compare the speech input to recorded letters that had been output to determine the correctness of the speech input. Alternatively, a clinician may administer the tests, e.g., offline.
  • If the results show a decline in motor, cognitive, and/or motor-cognitive function, the clinician may input a new target VTA, so that the method returns to step 702. Otherwise, the method may end.
  • In an example embodiment, the system may be preconfigured with predefined metrics concerning results of the administered tests, indicating acceptable results and unacceptable results. For example, the system may be configured with such indications concerning TWR, RRMSE, and DTLs with respect to motor and/or cognitive skill as appropriate. In response to unacceptable results, the system may (as reflected by the broken lines) automatically cycle back to, for example, step 704 to determine a new set of parameters and associated estimated VTA which may improve such patient functions. For example, the system may select parameters that produce a VTA with less stimulation of non-motor regions of the brain or whose edges are further from such regions of the brain.
  • According to an example embodiment, the system and method may record and visually identify which explored VTAs were associated with a side effect. The clinician may identify a VTA for which there are subpar results of the described tests as such VTAs. Additionally or alternatively, the system may automatically record such VTAs as being associated with a side effect.
  • Such recordation may be helpful in that, for example, the system may output a GUI showing explored regions and indicate which of those have been associated side effects, so that the clinician has more information on which to base selection of stimulation parameters during subsequent stimulation sessions.
  • In an example embodiment of the present invention, after determining the stimulation parameter settings, e.g., based on automatic or manual selection of parameters corresponding to a VTA that is closest to a target VTA that avoids the non-motor regions of the brain, and or based on results of motor function, cognitive function, and dual motor-cognitive function tests, a voltage of an electrode may be decreased if a selected voltage is determined to cause a tingling sensation in the patient stimulated with the determined stimulation parameters.
  • While is has been reported that when memory demands of a task were increased, PD patients with bilateral STN DBS exhibited deficits in working memory (Hershey et al., 2004), it has been determined that unilateral STN DBS has little effect on working memory as n-back performance was similar during unilateral stimulation to that when patients were off DBS (Alberts et al., 2008). In the current study, with respect to bilateral STN DBS, n-back performance at the most difficult condition (2-back) was compromised to a greater degree under Clinical DBS than under Model DBS or when Off DBS. These data suggest that minimizing current spread to the non-motor regions of the STN may alleviate some of the declines in working memory that may be associated with bilateral STN DBS. While the use of Model parameters did mitigate working memory declines, compared to Clinical parameters, working memory during bilateral STN DBS with Model parameters was not better than performance during unilateral STN DBS (Alberts et al., 2008). The observation that cognitive functioning (working memory) during unilateral DBS was better than bilateral STN DBS, whether Model or Clinical based, provides a rationale for taking a more conservative approach to the implantation of DBS systems.
  • Therefore, according to an example embodiment of the present invention, a stimulation method may include implementing a staged DBS implantation strategy, by initially performing unilateral DBS, assessing the impact of the unilateral DBS, e.g., on cognitive function, and subsequently implanting the second side. Such a method may decrease the likelihood of cognitive declines that can be associated with bilateral STN DBS and which may ultimately diminish the patient's overall quality of life. For example, the unilateral DBS may be determined to be sufficiently effective, and the bilateral DBS may be delayed for 6-12 months or even as long as 5 years. thereby delaying the increased cognitive impairment that is a result of the bilateral DBS.
  • In the event of inconsistent usages between this document and those documents incorporated by reference herein, the usage in the incorporated reference(s) should be considered supplementary to that of this document; and for irreconcilable inconsistencies, the usage in this document controls.
  • The above description is intended to be illustrative, and not restrictive. Those skilled in the art can appreciate from the foregoing description that the present invention may be implemented in a variety of forms, and that the various embodiments may be implemented alone or in combination. Therefore, while the embodiments of the present invention have been described in connection with particular examples thereof, the true scope of the embodiments and/or methods of the present invention should not be so limited since other modifications will become apparent to the skilled practitioner upon a study of the drawings, specification, and following claims. For example, while example embodiments discussed in detail refer to PD patients, embodiments of the present invention, for example, pertaining to selection of stimulation parameters based on monitoring of cognitive function, motor function, and combination thereof, may be applied to patients having other neuro-degenerative diseases, including neuro-motor diseases or neuro-cognitive diseases.

Claims (7)

1. A method, comprising:
using deep brain stimulation, stimulating at least one of the zona incerta, lenticular fasciculus, and motor region of the globus pallidus, wherein less than 10% of non-motor regions of the brain is stimulated as a result of the stimulation.
2. The method of claim 1, wherein less than 10% of the non-motor regions of the globus pallidus is stimulated as a result of the stimulation.
3. A method, comprising:
stimulating an anatomical region in a stimulation procedure in which at least one of the zona incerta, lenticular fasciculus, and motor region of the globus pallidus are stimulated, while current is not spread to, and therefore there is no stimulation of, any of the corticospinal tract (CS), corticobulbar tract (CB), and the non-motor regions of the globus pallidus (GP).
4. A method, comprising:
selecting stimulation parameters for treatment of a neuro-degenerative disorder based on results of tests of cognitive function, tests of motor function, and a combination of such tests, the tests being conducted on by the patient to which stimulation is to be performed using the selected stimulation parameters.
5. The method of claim 4, wherein the stimulation is performed using implanted electrodes.
6. The method of claim 4, wherein the test results are used for selection of stimulation parameters that minimize creep of current to non-motor anatomic regions.
7. The method of claim 6, wherein an n-Back test is used as the test for testing cognitive function, a force-maintenance task is used as the test for testing motor function, and a test where the patient is subjected to both the n-Back test and the force-maintenance task simultaneously is used as the combination.
US12/986,735 2009-12-02 2011-01-07 Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming Abandoned US20110184487A1 (en)

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120116211A1 (en) * 2010-10-19 2012-05-10 The Cleveland Clinic Foundation Methods for identifying target stimulation regions associated with therapeutic and non-therapeutic clinical outcomes for neural stimulation
US20150031005A1 (en) * 2013-07-24 2015-01-29 Ross Alloway Method of Training Verbal and/or Visual Information Processing By Executing Computer-Executable Instructions Stored On a Non-Transitory Computer-Readable Medium
US9501829B2 (en) 2011-03-29 2016-11-22 Boston Scientific Neuromodulation Corporation System and method for atlas registration
US9526902B2 (en) 2008-05-15 2016-12-27 Boston Scientific Neuromodulation Corporation VOA generation system and method using a fiber specific analysis
US9545510B2 (en) 2008-02-12 2017-01-17 Intelect Medical, Inc. Directional lead assembly with electrode anchoring prongs
US9561380B2 (en) 2012-08-28 2017-02-07 Boston Scientific Neuromodulation Corporation Point-and-click programming for deep brain stimulation using real-time monopolar review trendlines
US9592389B2 (en) 2011-05-27 2017-03-14 Boston Scientific Neuromodulation Corporation Visualization of relevant stimulation leadwire electrodes relative to selected stimulation information
US9604067B2 (en) 2012-08-04 2017-03-28 Boston Scientific Neuromodulation Corporation Techniques and methods for storing and transferring registration, atlas, and lead information between medical devices
US9713722B1 (en) 2016-04-29 2017-07-25 Medtronic Bakken Research Center B.V. Alternative electrode configurations for reduced power consumption
US9717459B2 (en) 2013-03-04 2017-08-01 Anne Bibiana Sereno Touch sensitive system and method for cognitive and behavioral testing and evaluation
US9760688B2 (en) 2004-07-07 2017-09-12 Cleveland Clinic Foundation Method and device for displaying predicted volume of influence
US9776003B2 (en) 2009-12-02 2017-10-03 The Cleveland Clinic Foundation Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming
US9792412B2 (en) 2012-11-01 2017-10-17 Boston Scientific Neuromodulation Corporation Systems and methods for VOA model generation and use
US9867989B2 (en) 2010-06-14 2018-01-16 Boston Scientific Neuromodulation Corporation Programming interface for spinal cord neuromodulation
US9925382B2 (en) 2011-08-09 2018-03-27 Boston Scientific Neuromodulation Corporation Systems and methods for stimulation-related volume analysis, creation, and sharing
US9959388B2 (en) 2014-07-24 2018-05-01 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for providing electrical stimulation therapy feedback
US9956419B2 (en) 2015-05-26 2018-05-01 Boston Scientific Neuromodulation Corporation Systems and methods for analyzing electrical stimulation and selecting or manipulating volumes of activation
US9974959B2 (en) 2014-10-07 2018-05-22 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for electrical stimulation using feedback to adjust stimulation parameters
US10071249B2 (en) 2015-10-09 2018-09-11 Boston Scientific Neuromodulation Corporation System and methods for clinical effects mapping for directional stimulation leads
US10265528B2 (en) 2014-07-30 2019-04-23 Boston Scientific Neuromodulation Corporation Systems and methods for electrical stimulation-related patient population volume analysis and use
US10272247B2 (en) 2014-07-30 2019-04-30 Boston Scientific Neuromodulation Corporation Systems and methods for stimulation-related volume analysis, creation, and sharing with integrated surgical planning and stimulation programming
US10350404B2 (en) 2016-09-02 2019-07-16 Boston Scientific Neuromodulation Corporation Systems and methods for visualizing and directing stimulation of neural elements
US10360511B2 (en) 2005-11-28 2019-07-23 The Cleveland Clinic Foundation System and method to estimate region of tissue activation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090118635A1 (en) * 2007-11-06 2009-05-07 The Cleveland Clinic Foundation Automated 3d brain atlas fitting using intra-operative neurophysiological data
US20090118786A1 (en) * 2007-11-02 2009-05-07 Advanced Bionics Corporation Automated fitting system for deep brain stimulation

Family Cites Families (246)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3999555A (en) 1975-10-28 1976-12-28 Medtronic, Inc. Atrial pinch on lead and insertion tool
AR216293A1 (en) 1976-12-02 1979-12-14 Leon De Pedro F Dientecillos auto fixable electrode and a clamp for maneuver
US4144889A (en) 1977-05-31 1979-03-20 Research Corporation Cardiac electrodes for temporary pacing
US4445500A (en) 1982-03-03 1984-05-01 Thomas Jefferson University Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4378797A (en) 1980-04-14 1983-04-05 Thomas Jefferson University Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US4341221A (en) 1980-10-07 1982-07-27 Medtronic, Inc. Shielded recording electrode system
US4765341A (en) 1981-06-22 1988-08-23 Mieczyslaw Mirowski Cardiac electrode with attachment fin
US4735208B1 (en) 1987-01-09 1995-07-04 Ad Tech Medical Instr Corp Subdural strip electrode for determining epileptogenic foci
US4841973A (en) 1987-09-21 1989-06-27 Stecker Harold D Electrical stimulators
US5067495A (en) 1989-09-27 1991-11-26 Brehm Richard L Electro wave therapy
US5255693A (en) 1989-11-02 1993-10-26 Possis Medical, Inc. Cardiac lead
US5222494A (en) 1991-07-31 1993-06-29 Cyberonics, Inc. Implantable tissue stimulator output stabilization system
US5259387A (en) 1991-09-09 1993-11-09 Quinton Instrument Company ECG muscle artifact filter system
US5304206A (en) 1991-11-18 1994-04-19 Cyberonics, Inc. Activation techniques for implantable medical device
US5560360A (en) 1992-03-09 1996-10-01 University Of Washington Image neurography and diffusion anisotropy imaging
US5603318A (en) 1992-04-21 1997-02-18 University Of Utah Research Foundation Apparatus and method for photogrammetric surgical localization
US5370675A (en) 1992-08-12 1994-12-06 Vidamed, Inc. Medical probe device and method
US6096756A (en) 1992-09-21 2000-08-01 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
GB9302335D0 (en) 1993-02-05 1993-03-24 Macdonald Alexander J R Electrotherapeutic apparatus
US5344438A (en) 1993-04-16 1994-09-06 Medtronic, Inc. Cuff electrode
US5601612A (en) 1993-08-06 1997-02-11 Heartstream, Inc. Method for applying a multiphasic waveform
US5607454A (en) 1993-08-06 1997-03-04 Heartstream, Inc. Electrotherapy method and apparatus
US6129685A (en) 1994-02-09 2000-10-10 The University Of Iowa Research Foundation Stereotactic hypothalamic obesity probe
US5651767A (en) 1994-05-06 1997-07-29 Alfred F. Mann Foundation For Scientific Research Replaceable catheter system for physiological sensors, stimulating electrodes and/or implantable fluid delivery systems
DE19525570A1 (en) 1994-07-13 1996-01-18 Fraunhofer Ges Forschung Flexible, non-conducting, artificial, implantable nerve plate
US5682468A (en) 1995-01-23 1997-10-28 Intergraph Corporation OLE for design and modeling
US6435878B1 (en) 1997-02-27 2002-08-20 Bci, Llc Interactive computer program for measuring and analyzing mental ability
US5868740A (en) 1995-03-24 1999-02-09 Board Of Regents-Univ Of Nebraska Method for volumetric tissue ablation
US5565949A (en) 1995-07-10 1996-10-15 Kasha, Jr.; John R. Visual field perimetry on a small computer screen
US5925070A (en) 1996-04-04 1999-07-20 Medtronic, Inc. Techniques for adjusting the locus of excitation of electrically excitable tissue
US5716377A (en) 1996-04-25 1998-02-10 Medtronic, Inc. Method of treating movement disorders by brain stimulation
US5713922A (en) 1996-04-25 1998-02-03 Medtronic, Inc. Techniques for adjusting the locus of excitation of neural tissue in the spinal cord or brain
US6094598A (en) 1996-04-25 2000-07-25 Medtronics, Inc. Method of treating movement disorders by brain stimulation and drug infusion
US5711316A (en) 1996-04-30 1998-01-27 Medtronic, Inc. Method of treating movement disorders by brain infusion
US5938690A (en) 1996-06-07 1999-08-17 Advanced Neuromodulation Systems, Inc. Pain management system and method
US6609031B1 (en) 1996-06-07 2003-08-19 Advanced Neuromodulation Systems, Inc. Multiprogrammable tissue stimulator and method
US6246912B1 (en) 1996-06-27 2001-06-12 Sherwood Services Ag Modulated high frequency tissue modification
US5843148A (en) 1996-09-27 1998-12-01 Medtronic, Inc. High resolution brain stimulation lead and method of use
US6029090A (en) 1997-01-27 2000-02-22 Herbst; Ewa Multi-functional electrical stimulation system
US5859922A (en) 1997-02-21 1999-01-12 Hoffmann; Kenneth R. Process of determining the three-dimensional location of a pacemaker leads in the heart of a subject
US5843146A (en) 1997-04-30 1998-12-01 Medtronic Incorporated Adjustable medical lead anchor
US6050992A (en) 1997-05-19 2000-04-18 Radiotherapeutics Corporation Apparatus and method for treating tissue with multiple electrodes
US6258084B1 (en) 1997-09-11 2001-07-10 Vnus Medical Technologies, Inc. Method for applying energy to biological tissue including the use of tumescent tissue compression
US6016449A (en) 1997-10-27 2000-01-18 Neuropace, Inc. System for treatment of neurological disorders
US5978713A (en) 1998-02-06 1999-11-02 Intermedics Inc. Implantable device with digital waveform telemetry
US6205361B1 (en) 1998-02-10 2001-03-20 Advanced Bionics Corporation Implantable expandable multicontact electrodes
US6192266B1 (en) 1998-03-26 2001-02-20 Boston Scientific Corporation Systems and methods for controlling the use of diagnostic or therapeutic instruments in interior body regions using real and idealized images
US6058331A (en) 1998-04-27 2000-05-02 Medtronic, Inc. Apparatus and method for treating peripheral vascular disease and organ ischemia by electrical stimulation with closed loop feedback control
US6421566B1 (en) 1998-04-30 2002-07-16 Medtronic, Inc. Selective dorsal column stimulation in SCS, using conditioning pulses
AU4959799A (en) 1998-06-26 2000-01-17 Advanced Bionics Corporation Programmable current output stimulus stage for implantable device
US6029091A (en) 1998-07-09 2000-02-22 Irvine Biomedical, Inc. Catheter system having lattice electrodes
US6366813B1 (en) 1998-08-05 2002-04-02 Dilorenzo Daniel J. Apparatus and method for closed-loop intracranical stimulation for optimal control of neurological disease
JP3330090B2 (en) 1998-09-30 2002-09-30 松下電器産業株式会社 Organ boundary extraction method and apparatus
JP4443672B2 (en) 1998-10-14 2010-03-31 株式会社東芝 The ultrasonic diagnostic apparatus
US6208881B1 (en) 1998-10-20 2001-03-27 Micropure Medical, Inc. Catheter with thin film electrodes and method for making same
US6253109B1 (en) 1998-11-05 2001-06-26 Medtronic Inc. System for optimized brain stimulation
US6161044A (en) 1998-11-23 2000-12-12 Synaptic Corporation Method and apparatus for treating chronic pain syndromes, tremor, dementia and related disorders and for inducing electroanesthesia using high frequency, high intensity transcutaneous electrical nerve stimulation
US6393325B1 (en) 1999-01-07 2002-05-21 Advanced Bionics Corporation Directional programming for implantable electrode arrays
US6368331B1 (en) 1999-02-22 2002-04-09 Vtarget Ltd. Method and system for guiding a diagnostic or therapeutic instrument towards a target region inside the patient's body
US6606523B1 (en) 1999-04-14 2003-08-12 Transneuronix Inc. Gastric stimulator apparatus and method for installing
US6579280B1 (en) 1999-04-30 2003-06-17 Medtronic, Inc. Generic multi-step therapeutic treatment protocol
US6134477A (en) 1999-04-30 2000-10-17 Medtronic, Inc. Adjustable medical lead fixation system
US6353762B1 (en) 1999-04-30 2002-03-05 Medtronic, Inc. Techniques for selective activation of neurons in the brain, spinal cord parenchyma or peripheral nerve
US6109269A (en) 1999-04-30 2000-08-29 Medtronic, Inc. Method of treating addiction by brain infusion
EP1191972B1 (en) 1999-06-11 2005-08-31 Cornell Research Foundation, Inc. Feedback mechanism for deep brain stimulation
US6539263B1 (en) 1999-06-11 2003-03-25 Cornell Research Foundation, Inc. Feedback mechanism for deep brain stimulation
US6167311A (en) 1999-06-14 2000-12-26 Electro Core Techniques, Llc Method of treating psychological disorders by brain stimulation within the thalamus
WO2000077760A1 (en) 1999-06-15 2000-12-21 Dimitri Caplygin System for enhancement of neurophysiological processes
FR2795229B1 (en) 1999-06-17 2001-08-03 Ferraz Jawbone to fuse and fuse holder team of such jaw
US6343226B1 (en) 1999-06-25 2002-01-29 Neurokinetic Aps Multifunction electrode for neural tissue stimulation
US6516227B1 (en) 1999-07-27 2003-02-04 Advanced Bionics Corporation Rechargeable spinal cord stimulator system
US6494831B1 (en) 1999-09-03 2002-12-17 Ge Medical Technology Services, Inc. Medical diagnostic system service connectivity method and apparatus
US7047082B1 (en) 1999-09-16 2006-05-16 Micronet Medical, Inc. Neurostimulating lead
US6654642B2 (en) 1999-09-29 2003-11-25 Medtronic, Inc. Patient interactive neurostimulation system and method
US7949395B2 (en) 1999-10-01 2011-05-24 Boston Scientific Neuromodulation Corporation Implantable microdevice with extended lead and remote electrode
AU1547101A (en) 1999-11-26 2001-06-04 Applied Spectral Imaging Ltd. System and method for functional brain mapping and an oxygen saturation difference map algorithm for effecting same
US6442432B2 (en) 1999-12-21 2002-08-27 Medtronic, Inc. Instrumentation and software for remote monitoring and programming of implantable medical devices (IMDs)
DE19963468A1 (en) 1999-12-29 2001-07-05 Bosch Gmbh Robert Method for controlling an element of a drive train of a vehicle and control unit for carrying out
DE60018978T2 (en) 1999-12-30 2006-05-04 Medtronic, Inc., Minneapolis User authentication in medical systems
US6885888B2 (en) 2000-01-20 2005-04-26 The Cleveland Clinic Foundation Electrical stimulation of the sympathetic nerve chain
US6301492B1 (en) 2000-01-20 2001-10-09 Electrocore Technologies, Llc Device for performing microelectrode recordings through the central channel of a deep-brain stimulation electrode
US6609029B1 (en) 2000-02-04 2003-08-19 Advanced Bionics Corporation Clip lock mechanism for retaining lead
US6708064B2 (en) 2000-02-24 2004-03-16 Ali R. Rezai Modulation of the brain to affect psychiatric disorders
US6741892B1 (en) 2000-03-10 2004-05-25 Advanced Bionics Corporation Movable contact locking mechanism for spinal cord stimulator lead connector
US6778846B1 (en) 2000-03-30 2004-08-17 Medtronic, Inc. Method of guiding a medical device and system regarding same
US6944501B1 (en) 2000-04-05 2005-09-13 Neurospace, Inc. Neurostimulator involving stimulation strategies and process for using it
US6466822B1 (en) 2000-04-05 2002-10-15 Neuropace, Inc. Multimodal neurostimulator and process of using it
US7082333B1 (en) 2000-04-27 2006-07-25 Medtronic, Inc. Patient directed therapy management
US6631297B1 (en) 2000-05-18 2003-10-07 Seung-Kee Mo Electrical clinical apparatus and electrical stimulation method using variant assignment method
US7818185B2 (en) 2000-06-02 2010-10-19 Qualitymetric Incorporated Method, system and medium for assessing the impact of various ailments on health related quality of life
US6748276B1 (en) 2000-06-05 2004-06-08 Advanced Neuromodulation Systems, Inc. Neuromodulation therapy system
US6324435B1 (en) 2000-06-22 2001-11-27 Ethicon, Inc. Electrical connector for cardiac devices
US20020115603A1 (en) 2000-06-22 2002-08-22 Chiron Corporation Methods and compositions for the treatment of peripheral artery disease
US7305268B2 (en) 2000-07-13 2007-12-04 Northstar Neurscience, Inc. Systems and methods for automatically optimizing stimulus parameters and electrode configurations for neuro-stimulators
US7299096B2 (en) 2001-03-08 2007-11-20 Northstar Neuroscience, Inc. System and method for treating Parkinson's Disease and other movement disorders
US7010351B2 (en) 2000-07-13 2006-03-07 Northstar Neuroscience, Inc. Methods and apparatus for effectuating a lasting change in a neural-function of a patient
US6510347B2 (en) 2000-08-17 2003-01-21 William N. Borkan Spinal cord stimulation leads
US6662053B2 (en) 2000-08-17 2003-12-09 William N. Borkan Multichannel stimulator electronics and methods
US6885886B2 (en) 2000-09-11 2005-04-26 Brainlab Ag Method and system for visualizing a body volume and computer program product
US20020032375A1 (en) 2000-09-11 2002-03-14 Brainlab Ag Method and system for visualizing a body volume and computer program product
US6560490B2 (en) 2000-09-26 2003-05-06 Case Western Reserve University Waveforms for selective stimulation of central nervous system neurons
US6985774B2 (en) 2000-09-27 2006-01-10 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US6845267B2 (en) 2000-09-28 2005-01-18 Advanced Bionics Corporation Systems and methods for modulation of circulatory perfusion by electrical and/or drug stimulation
US6517480B1 (en) 2000-10-04 2003-02-11 Alvin Krass Neurological testing apparatus
WO2002028473A1 (en) 2000-10-04 2002-04-11 Cochlear Limited Cochlear implant electrode array
US8509887B2 (en) 2000-11-20 2013-08-13 Eleanor Schuler Method to record, store and broadcast specific brain waveforms to modulate body organ functioning
US7308302B1 (en) 2000-11-20 2007-12-11 Schuler Eleanor L Device and method to record, store and broadcast specific brain waveforms to modulate body organ functioning
US20050251061A1 (en) 2000-11-20 2005-11-10 Schuler Eleanor L Method and system to record, store and transmit waveform signals to regulate body organ function
US6950707B2 (en) 2000-11-21 2005-09-27 Advanced Bionics Corporation Systems and methods for treatment of obesity and eating disorders by electrical brain stimulation and/or drug infusion
DE60124948T2 (en) 2000-12-07 2007-09-20 Medtronic, Inc., Minneapolis Lines for directed brain stimulation and recording
US7389145B2 (en) 2001-02-20 2008-06-17 Case Western Reserve University Systems and methods for reversibly blocking nerve activity
US6775573B2 (en) 2001-03-01 2004-08-10 Science Medicus Inc. Electrical method to control autonomic nerve stimulation of gastrointestinal tract
WO2002072192A2 (en) 2001-03-08 2002-09-19 Medtronic, Inc. Lead with adjustable angular and spatial relationships between electrodes
EP2263745A1 (en) 2001-03-30 2010-12-22 Case Western Reserve University Systems for selectively stimulating components in, on, or near the pudendal nerve or its branches to achieve selective physiologic responses
US7054692B1 (en) 2001-06-22 2006-05-30 Advanced Bionics Corporation Fixation device for implantable microdevices
EP1417000B1 (en) 2001-07-11 2018-07-11 Nuvasive, Inc. System for determining nerve proximity during surgery
US6675049B2 (en) 2001-07-17 2004-01-06 Medtronic, Inc. Method and apparatus for automatic implantable medical lead recognition and configuration
US6600956B2 (en) 2001-08-21 2003-07-29 Cyberonics, Inc. Circumneural electrode assembly
US20050143169A1 (en) 2001-09-20 2005-06-30 Igt Direction interfaces and services on a gaming machine
US6944497B2 (en) 2001-10-31 2005-09-13 Medtronic, Inc. System and method of treating stuttering by neuromodulation
WO2003045222A2 (en) 2001-11-21 2003-06-05 Viatronix Incorporated System and method for visualization and navigation of three-dimensional medical images
WO2003063951A1 (en) 2002-01-29 2003-08-07 Advanced Bionics Corporation Lead assembly for implantable microstimulator
US20030149450A1 (en) 2002-02-01 2003-08-07 Mayberg Marc R. Brainstem and cerebellar modulation of cardiovascular response and disease
US6990639B2 (en) 2002-02-07 2006-01-24 Microsoft Corporation System and process for controlling electronic components in a ubiquitous computing environment using multimodal integration
US7043305B2 (en) 2002-03-06 2006-05-09 Cardiac Pacemakers, Inc. Method and apparatus for establishing context among events and optimizing implanted medical device performance
US7136696B2 (en) 2002-04-05 2006-11-14 The Cleveland Clinic Foundation Neuron signal analysis system and method
US6937891B2 (en) 2002-04-26 2005-08-30 Medtronic, Inc. Independent therapy programs in an implantable medical device
ES2426255T3 (en) 2002-06-28 2013-10-22 Boston Scientific Neuromodulation Corporation Microstimulator that has a built-in power source and a two-way telemetry system
US7228179B2 (en) 2002-07-26 2007-06-05 Advanced Neuromodulation Systems, Inc. Method and apparatus for providing complex tissue stimulation patterns
US7277748B2 (en) 2002-09-13 2007-10-02 Neuropace, Inc. Spatiotemporal pattern recognition for neurological event detection and prediction in an implantable device
KR20050062773A (en) 2002-10-09 2005-06-27 보디미디어 인코퍼레이티드 Method and apparatus for auto journaling of continuous or discrete body states utilizing physiological and/or contextual parameters
EP1578487B1 (en) 2002-10-15 2012-01-25 Medtronic, Inc. Channel-selective blanking for a medical device system
US20050049649A1 (en) 2002-10-21 2005-03-03 The Cleveland Clinic Foundation Electrical stimulation of the brain
AU2003288959A1 (en) 2002-10-31 2004-06-07 Medtronic, Inc. Body region indication
US7216000B2 (en) 2002-10-31 2007-05-08 Medtronic, Inc. Neurostimulation therapy manipulation
US7047084B2 (en) 2002-11-20 2006-05-16 Advanced Neuromodulation Systems, Inc. Apparatus for directionally stimulating nerve tissue
AU2003297761A1 (en) 2002-12-09 2004-06-30 Northstar Neuroscience, Inc. Methods for treating neurological language disorders
US7236830B2 (en) 2002-12-10 2007-06-26 Northstar Neuroscience, Inc. Systems and methods for enhancing or optimizing neural stimulation therapy for treating symptoms of Parkinson's disease and/or other movement disorders
AU2004204674A1 (en) 2003-01-03 2004-07-29 Advanced Neuromodulation Systems, Inc. System and method for stimulation of a person's brain stem
EP1586020A2 (en) 2003-01-25 2005-10-19 Purdue Research Foundation Methods, systems, and data structures for performing searches on three dimensional objects
WO2004075982A1 (en) 2003-02-21 2004-09-10 Medtronic, Inc. Implantable neurostimulator programming with battery longevity indication
US7347818B2 (en) 2003-02-24 2008-03-25 Neurotrax Corporation Standardized medical cognitive assessment tool
US7647116B2 (en) 2003-03-13 2010-01-12 Medtronic, Inc. Context-sensitive collection of neurostimulation therapy data
US7450983B2 (en) 2003-03-18 2008-11-11 University Of Cincinnati Automated brain MRI and CT prescriptions in Talairach space
US7167760B2 (en) 2003-04-28 2007-01-23 Vanderbilt University Apparatus and methods of optimal placement of deep brain stimulator
US20050261747A1 (en) 2003-05-16 2005-11-24 Schuler Eleanor L Method and system to control respiration by means of neuro-electrical coded signals
WO2004103459A2 (en) 2003-05-16 2004-12-02 Science Medicus, Inc. Respiratory control by means of neuro-electrical coded signals
JP4174825B2 (en) 2003-05-23 2008-11-05 株式会社テクノリンク Biostimulator
US20050288732A1 (en) 2003-06-18 2005-12-29 Eleanor Schuler Method and system to control skeletal muscles by means of neuro-electrical coded signals
WO2005007234A2 (en) 2003-07-10 2005-01-27 Science Medicus, Inc. Regulation of endocrine and exocrine glands by means of neuro-electrical coded signals
MXPA06000758A (en) 2003-07-23 2006-03-30 Science Medicus Inc Method and device for regulation of limbic system of the brain by means of neuro-electrical coded signals.
US8725246B2 (en) 2003-07-23 2014-05-13 Eleanor Schuler Method and system for modulating eating behavior by means of neuro-electrical coded signals
US7711431B2 (en) 2003-08-04 2010-05-04 Brainlab Ag Method and device for stimulating the brain
US7239926B2 (en) 2003-09-15 2007-07-03 Medtronic, Inc. Selection of neurostimulator parameter configurations using genetic algorithms
US7729766B2 (en) 2003-10-02 2010-06-01 Medtronic, Inc. Circuit board construction for handheld programmer
US7835778B2 (en) 2003-10-16 2010-11-16 Medtronic Navigation, Inc. Method and apparatus for surgical navigation of a multiple piece construct for implantation
US20060069415A1 (en) 2003-11-20 2006-03-30 Advanced Neuromodulation Systems, Inc. Electrical stimulation system, lead, and method providing modified reduced neuroplasticity effect
US20060004422A1 (en) 2004-03-11 2006-01-05 Dirk De Ridder Electrical stimulation system and method for stimulating tissue in the brain to treat a neurological condition
US20050267347A1 (en) 2004-05-04 2005-12-01 Doran Oster Deep brain stimulation
DE102004025945A1 (en) 2004-05-27 2005-12-29 Forschungszentrum Jülich GmbH Method and device for the decoupling and / or desynchronization of neuronal brain activity
CA2569877A1 (en) 2004-06-10 2005-12-29 Science Medicus, Inc. Method and system for processing neuro-electrical waveform signals
US7346382B2 (en) 2004-07-07 2008-03-18 The Cleveland Clinic Foundation Brain stimulation models, systems, devices, and methods
US7819909B2 (en) 2004-07-20 2010-10-26 Medtronic, Inc. Therapy programming guidance based on stored programming history
US20100331883A1 (en) 2004-10-15 2010-12-30 Schmitz Gregory P Access and tissue modification systems and methods
US7734340B2 (en) 2004-10-21 2010-06-08 Advanced Neuromodulation Systems, Inc. Stimulation design for neuromodulation
US8019439B2 (en) 2005-01-11 2011-09-13 Boston Scientific Neuromodulation Corporation Lead assembly and method of making same
EP1853344A4 (en) 2005-03-02 2008-05-28 Continence Control Systems Int Improved method and apparatus for treating incontinence
US7519431B2 (en) 2005-04-11 2009-04-14 Medtronic, Inc. Shifting between electrode combinations in electrical stimulation device
WO2006113305A2 (en) 2005-04-13 2006-10-26 The Cleveland Clinic Foundation System and method for providing a waveform for stimulating biological tissue
US7715912B2 (en) 2005-04-13 2010-05-11 Intelect Medical, Inc. System and method for providing a waveform for stimulating biological tissue
US7769472B2 (en) 2005-07-29 2010-08-03 Medtronic, Inc. Electrical stimulation lead with conformable array of electrodes
US8620636B2 (en) 2005-08-25 2013-12-31 Schlumberger Technology Corporation Interpreting well test measurements
US8374696B2 (en) 2005-09-14 2013-02-12 University Of Florida Research Foundation, Inc. Closed-loop micro-control system for predicting and preventing epileptic seizures
US7761165B1 (en) 2005-09-29 2010-07-20 Boston Scientific Neuromodulation Corporation Implantable stimulator with integrated plastic housing/metal contacts and manufacture and use
US7650184B2 (en) 2005-12-01 2010-01-19 Boston Scientific Neuromodulation Corporation Cylindrical multi-contact electrode lead for neural stimulation and method of making same
US20070135855A1 (en) 2005-12-13 2007-06-14 Foshee Phillip D Patient management device for portably interfacing with a plurality of implantable medical devices and method thereof
US20080133141A1 (en) 2005-12-22 2008-06-05 Frost Stephen J Weighted Scoring Methods and Use Thereof in Screening
US8700178B2 (en) 2005-12-27 2014-04-15 Boston Scientific Neuromodulation Corporation Stimulator leads and methods for lead fabrication
US7672734B2 (en) 2005-12-27 2010-03-02 Boston Scientific Neuromodulation Corporation Non-linear electrode array
US7244150B1 (en) 2006-01-09 2007-07-17 Advanced Bionics Corporation Connector and methods of fabrication
US7869854B2 (en) 2006-02-23 2011-01-11 Magnetecs, Inc. Apparatus for magnetically deployable catheter with MOSFET sensor and method for mapping and ablation
US7657319B2 (en) 2006-02-24 2010-02-02 Medtronic, Inc. Programming interface with an unwrapped 2D view of a stimulation lead with complex electrode array geometry
US8452415B2 (en) 2006-02-24 2013-05-28 Medtronic, Inc. Electrical and activation field models for programming a stimulation lead with complex electrode array geometry
US7822483B2 (en) * 2006-02-24 2010-10-26 Medtronic, Inc. Electrical and activation field models for configuring stimulation therapy
US8380321B2 (en) 2006-02-24 2013-02-19 Medtronic, Inc. Programming interface with a cross-sectional view of a stimulation lead with complex electrode array geometry
WO2007103475A2 (en) 2006-03-07 2007-09-13 Beth Israel Deaconess Medical Center, Inc. Transcranial magnetic stimulation (tms) methods and apparatus
US8180601B2 (en) 2006-03-09 2012-05-15 The Cleveland Clinic Foundation Systems and methods for determining volume of activation for deep brain stimulation
US8606360B2 (en) 2006-03-09 2013-12-10 The Cleveland Clinic Foundation Systems and methods for determining volume of activation for spinal cord and peripheral nerve stimulation
US8175710B2 (en) 2006-03-14 2012-05-08 Boston Scientific Neuromodulation Corporation Stimulator system with electrode array and the method of making the same
US7974706B2 (en) 2006-03-30 2011-07-05 Boston Scientific Neuromodulation Corporation Electrode contact configurations for cuff leads
US7949401B2 (en) 2006-04-11 2011-05-24 Advanced Neuromodulation Systems, Inc. Electromagnetic signal delivery for tissue affected by neuronal dysfunction, degradation, damage, and/or necrosis, and associated systems and methods
US7715920B2 (en) 2006-04-28 2010-05-11 Medtronic, Inc. Tree-based electrical stimulator programming
WO2008005144A2 (en) 2006-06-30 2008-01-10 Medtronic, Inc. Selecting electrode combinations for stimulation therapy
US8160677B2 (en) 2006-09-08 2012-04-17 Medtronic, Inc. Method for identification of anatomical landmarks
US8224450B2 (en) 2006-09-18 2012-07-17 Boston Scientific Neuromodulation Corporation Feed through interconnect assembly for an implantable stimulation system and methods of making and using
US8214345B2 (en) 2006-10-05 2012-07-03 International Business Machines Corporation Custom constraints for faceted exploration
WO2008066891A2 (en) 2006-11-28 2008-06-05 Sensable Technologies, Inc. Systems for haptic design of dental restorations
US8798759B2 (en) 2006-12-06 2014-08-05 Medtronic, Inc. User interface with toolbar for programming electrical stimulation therapy
WO2008080126A2 (en) 2006-12-22 2008-07-03 Aviir, Inc. Two biomarkers for diagnosis and monitoring of atherosclerotic cardiovascular disease
US8014578B2 (en) 2007-02-05 2011-09-06 General Electric Company Method and system for image segmentation using models
US8401609B2 (en) 2007-02-14 2013-03-19 The Board Of Trustees Of The Leland Stanford Junior University System, method and applications involving identification of biological circuits such as neurological characteristics
US20080242950A1 (en) 2007-03-30 2008-10-02 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational user-health testing
US8543189B2 (en) 2007-04-23 2013-09-24 Medtronic Navigation, Inc. Method and apparatus for electromagnetic navigation of a magnetic stimulation probe
US8910638B2 (en) 2007-05-09 2014-12-16 Massachusetts Institute Of Technology Methods and apparatus for high-throughput neural screening
KR100897528B1 (en) 2007-06-22 2009-05-15 재단법인서울대학교산학협력재단 Method of determining the position of a deep brain stimulation electrode
JP2009018048A (en) 2007-07-12 2009-01-29 Fujifilm Corp Medical image display, method and program
EP2249916B1 (en) 2008-01-31 2011-11-02 Medtronic, Inc. Electrode-to-lead association using post-implant imaging
US20090242399A1 (en) 2008-03-25 2009-10-01 Dexcom, Inc. Analyte sensor
WO2009120836A1 (en) 2008-03-26 2009-10-01 Neurosigma, Inc. Methods for identifying and targeting autonomic brain regions
US7945105B1 (en) 2008-04-07 2011-05-17 Decision Sciences International Corporation Automated target shape detection for vehicle muon tomography
WO2010006304A2 (en) 2008-07-11 2010-01-14 Boston Scientific Neuromodulation Corporation System and method for converting tissue stimulation programs in a format usable by an electrical current steering navigator
US20100023103A1 (en) 2008-07-28 2010-01-28 Boston Scientific Neuromodulation Corporation Systems and Methods for Treating Essential Tremor or Restless Leg Syndrome Using Spinal Cord Stimulation
US20100030312A1 (en) 2008-07-31 2010-02-04 Xiaonan Shen Method and apparatus for lead length determination
US8262714B2 (en) 2008-08-05 2012-09-11 Advanced Neuromodulation Systems, Inc. Techniques for selecting signal delivery sites and other parameters for treating depression and other neurological disorders, and associated systems and methods
US20100064249A1 (en) 2008-09-05 2010-03-11 Gateway Inc. Visual indicator in GUI system for notifying user of data storage device
US20100121409A1 (en) 2008-11-12 2010-05-13 Sridhar Kothandaraman System and method for determining appropriate steering tables for distributing stimulation energy among multiple neurostimulation electrodes
US8995731B2 (en) 2008-11-26 2015-03-31 Medtronic, Inc. Image-based characterization of implanted medical leads
US8380301B2 (en) 2008-12-03 2013-02-19 Boston Scientific Neuromodulation Corporation Method and apparatus for determining relative positioning between neurostimulation leads
JP2012510877A (en) 2008-12-04 2012-05-17 ザ クリーブランド クリニック ファウンデーション System and method for defining a target volume for brain stimulation
EP2641633B1 (en) 2009-01-14 2018-04-04 Spinal Modulation Inc. Stimulation lead with stylet tube
US9095303B2 (en) 2009-03-23 2015-08-04 Flint Hills Scientific, Llc System and apparatus for early detection, prevention, containment or abatement of spread abnormal brain activity
US9597007B2 (en) 2009-07-21 2017-03-21 The Regents Of The University Of California Methods for the identification and targeting of brain regions and structures and treatments related thereto
JP5734295B2 (en) 2009-08-27 2015-06-17 ザ クリーブランド クリニック ファウンデーション System and method for estimating a site of tissue activity
WO2011068997A1 (en) 2009-12-02 2011-06-09 The Cleveland Clinic Foundation Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming
US8352039B2 (en) 2010-01-08 2013-01-08 Medtronic, Inc. Programming therapy delivered by implantable medical device
US8560080B2 (en) 2010-06-11 2013-10-15 Medtronic, Inc. Programming techniques for controlling rate of change of electrical stimulation therapy
US8862237B2 (en) 2010-06-14 2014-10-14 Boston Scientific Neuromodulation Corporation Programming interface for spinal cord neuromodulation
US8951192B2 (en) 2010-06-15 2015-02-10 Flint Hills Scientific, Llc Systems approach to disease state and health assessment
US8679009B2 (en) 2010-06-15 2014-03-25 Flint Hills Scientific, Llc Systems approach to comorbidity assessment
CA2808641A1 (en) 2010-08-18 2012-02-23 Boston Scientific Neuromodulation Corporation User interface for segmented neurostimulation leads
US8622913B2 (en) 2010-09-28 2014-01-07 General Electric Company Method and system for non-invasive monitoring of patient parameters
US9713721B2 (en) 2010-11-10 2017-07-25 Boston Scientific Neuromodulation Corporation System and method for storing application specific and lead configuration information in neurostimulation device
AU2011348126B2 (en) 2010-12-23 2016-03-10 Boston Scientific Neuromodulation Corporation Neurostimulation system for estimating desired stimulation amplitude for electrode configuration
WO2012092206A1 (en) 2010-12-27 2012-07-05 Boston Scientific Neuromodulation Corporation Neurostimulation system for selectively estimating volume of activation and providing therapy
US8488852B2 (en) 2011-02-15 2013-07-16 Siemens Aktiengesellschaft Medical imaging system for segementing blood vessel
US8994732B2 (en) 2011-03-07 2015-03-31 Microsoft Corporation Integration of sketch-based interaction and computer data analysis
EP2691896A2 (en) 2011-03-29 2014-02-05 Boston Scientific Neuromodulation Corporation Communication interface for therapeutic stimulation providing systems
AU2012262462B2 (en) 2011-05-27 2016-12-01 Boston Scientific Neuromodulation Corporation Collection of clinical data for graphical representation and analysis
WO2013023073A1 (en) 2011-08-09 2013-02-14 Boston Scientific Neuromodulation Corporation System and method for weighted atlas generation
EP2741817A2 (en) 2011-08-09 2014-06-18 Boston Scientific Neuromodulation Corporation Control and/or quantification of target stimulation volume overlap and interface therefor
CA2844075A1 (en) 2011-08-09 2013-02-14 Boston Scientific Neuromodulation Corporation Systems and methods for stimulation-related volume analysis, creation, and sharing
US9037256B2 (en) 2011-09-01 2015-05-19 Boston Scientific Neuromodulation Corporation Methods and system for targeted brain stimulation using electrical parameter maps
US9643017B2 (en) 2012-08-28 2017-05-09 Boston Scientific Neuromodulation Corporation Capture and visualization of clinical effects data in relation to a lead and/or locus of stimulation
US8918184B1 (en) 2013-03-12 2014-12-23 Medtronic, Inc. Identification of electrode combination for efficacious electrical stimulation therapy
US9474903B2 (en) 2013-03-15 2016-10-25 Boston Scientific Neuromodulation Corporation Clinical response data mapping
US9586053B2 (en) 2013-11-14 2017-03-07 Boston Scientific Neuromodulation Corporation Systems, methods, and visualization tools for stimulation and sensing of neural systems with system-level interaction models

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090118786A1 (en) * 2007-11-02 2009-05-07 Advanced Bionics Corporation Automated fitting system for deep brain stimulation
US20090118635A1 (en) * 2007-11-06 2009-05-07 The Cleveland Clinic Foundation Automated 3d brain atlas fitting using intra-operative neurophysiological data

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9760688B2 (en) 2004-07-07 2017-09-12 Cleveland Clinic Foundation Method and device for displaying predicted volume of influence
US10322285B2 (en) 2004-07-07 2019-06-18 Cleveland Clinic Foundation Method and device for displaying predicted volume of influence
US10360511B2 (en) 2005-11-28 2019-07-23 The Cleveland Clinic Foundation System and method to estimate region of tissue activation
US9545510B2 (en) 2008-02-12 2017-01-17 Intelect Medical, Inc. Directional lead assembly with electrode anchoring prongs
US9526902B2 (en) 2008-05-15 2016-12-27 Boston Scientific Neuromodulation Corporation VOA generation system and method using a fiber specific analysis
US9776003B2 (en) 2009-12-02 2017-10-03 The Cleveland Clinic Foundation Reversing cognitive-motor impairments in patients having a neuro-degenerative disease using a computational modeling approach to deep brain stimulation programming
US9867989B2 (en) 2010-06-14 2018-01-16 Boston Scientific Neuromodulation Corporation Programming interface for spinal cord neuromodulation
US8649845B2 (en) * 2010-10-19 2014-02-11 The Cleveland Clinic Foundation Methods for identifying target stimulation regions associated with therapeutic and non-therapeutic clinical outcomes for neural stimulation
US20120116211A1 (en) * 2010-10-19 2012-05-10 The Cleveland Clinic Foundation Methods for identifying target stimulation regions associated with therapeutic and non-therapeutic clinical outcomes for neural stimulation
US9501829B2 (en) 2011-03-29 2016-11-22 Boston Scientific Neuromodulation Corporation System and method for atlas registration
US9592389B2 (en) 2011-05-27 2017-03-14 Boston Scientific Neuromodulation Corporation Visualization of relevant stimulation leadwire electrodes relative to selected stimulation information
US9925382B2 (en) 2011-08-09 2018-03-27 Boston Scientific Neuromodulation Corporation Systems and methods for stimulation-related volume analysis, creation, and sharing
US9604067B2 (en) 2012-08-04 2017-03-28 Boston Scientific Neuromodulation Corporation Techniques and methods for storing and transferring registration, atlas, and lead information between medical devices
US10265532B2 (en) 2012-08-28 2019-04-23 Boston Scientific Neuromodulation Corporation Point-and-click programming for deep brain stimulation using real-time monopolar review trendlines
US9643017B2 (en) 2012-08-28 2017-05-09 Boston Scientific Neuromodulation Corporation Capture and visualization of clinical effects data in relation to a lead and/or locus of stimulation
US10016610B2 (en) 2012-08-28 2018-07-10 Boston Scientific Neuromodulation Corporation Point-and-click programming for deep brain stimulation using real-time monopolar review trendlines
US9561380B2 (en) 2012-08-28 2017-02-07 Boston Scientific Neuromodulation Corporation Point-and-click programming for deep brain stimulation using real-time monopolar review trendlines
US9821167B2 (en) 2012-08-28 2017-11-21 Boston Scientific Neuromodulation Corporation Point-and-click programming for deep brain stimulation using real-time monopolar review trendlines
US9959940B2 (en) 2012-11-01 2018-05-01 Boston Scientific Neuromodulation Corporation Systems and methods for VOA model generation and use
US9792412B2 (en) 2012-11-01 2017-10-17 Boston Scientific Neuromodulation Corporation Systems and methods for VOA model generation and use
US9717459B2 (en) 2013-03-04 2017-08-01 Anne Bibiana Sereno Touch sensitive system and method for cognitive and behavioral testing and evaluation
US20150031005A1 (en) * 2013-07-24 2015-01-29 Ross Alloway Method of Training Verbal and/or Visual Information Processing By Executing Computer-Executable Instructions Stored On a Non-Transitory Computer-Readable Medium
US9959388B2 (en) 2014-07-24 2018-05-01 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for providing electrical stimulation therapy feedback
US10272247B2 (en) 2014-07-30 2019-04-30 Boston Scientific Neuromodulation Corporation Systems and methods for stimulation-related volume analysis, creation, and sharing with integrated surgical planning and stimulation programming
US10265528B2 (en) 2014-07-30 2019-04-23 Boston Scientific Neuromodulation Corporation Systems and methods for electrical stimulation-related patient population volume analysis and use
US9974959B2 (en) 2014-10-07 2018-05-22 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for electrical stimulation using feedback to adjust stimulation parameters
US10357657B2 (en) 2014-10-07 2019-07-23 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for electrical stimulation using feedback to adjust stimulation parameters
US9956419B2 (en) 2015-05-26 2018-05-01 Boston Scientific Neuromodulation Corporation Systems and methods for analyzing electrical stimulation and selecting or manipulating volumes of activation
US10071249B2 (en) 2015-10-09 2018-09-11 Boston Scientific Neuromodulation Corporation System and methods for clinical effects mapping for directional stimulation leads
US9713722B1 (en) 2016-04-29 2017-07-25 Medtronic Bakken Research Center B.V. Alternative electrode configurations for reduced power consumption
US10350404B2 (en) 2016-09-02 2019-07-16 Boston Scientific Neuromodulation Corporation Systems and methods for visualizing and directing stimulation of neural elements

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