WO2010083208A2 - Traitement de maladies neuropsychiatriques - Google Patents

Traitement de maladies neuropsychiatriques Download PDF

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WO2010083208A2
WO2010083208A2 PCT/US2010/020890 US2010020890W WO2010083208A2 WO 2010083208 A2 WO2010083208 A2 WO 2010083208A2 US 2010020890 W US2010020890 W US 2010020890W WO 2010083208 A2 WO2010083208 A2 WO 2010083208A2
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stimulation
stimulus
dopamine
seconds
intermittent
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Kendall H. Lee
Charles D. Blaha
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Mayo Foundation For Medical Education And Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/326—Applying electric currents by contact electrodes alternating or intermittent currents for promoting growth of cells, e.g. bone cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease

Definitions

  • This document relates to methods and materials involved in treating neuropsychiatric diseases. For example, methods and materials for treating Parkinson's disease using deep brain stimulation are provided.
  • Parkinson's disease is the second most prevalent neurodegenerative disorder and affects approximately 1 million people in the U.S., with 50,000 diagnosed each year. Symptoms of this disorder include resting tremors in the appendages, loss of balance and slowness of gait (bradykinesia) and are due to a massive degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic neurons in this midbrain nucleus form the nigrostriatal dopaminergic system that projects to the basal ganglia (striatum in the rat) in the forebrain. Although the exact cause of the disorder is unknown, i.e., idiopathic, in most
  • PD patients there are cellular proteins that are overexpressed in the striatum.
  • Lewy body which is a fibrous protein that accumulates in striatal neuronal cell cytoplasm in PD patients (Shastry, "Parkinson disease: etiology, pathogenesis and future of gene therapy," Neurosci. Res., 41 : 5-12 (2001)).
  • certain genes ⁇ -synuclein, ubiquitin carboxy terminal hydrolase Ll (UCHLl) and parkin, a ubiquitin protein ligase
  • mutations in mitochondria and expression of gene-tau, a microtubule-associated protein have been found in families with PD.
  • This document relates to methods and materials involved in treating neuropsychiatric diseases.
  • methods and materials for treating Parkinson's disease (PD) using deep brain stimulation are provided.
  • the methods and materials provided herein can relieve motor symptoms associated with PD and extend battery life of a neurostimulator.
  • this document features a method for increasing dopamine release from the basal ganglia of a mammal.
  • the method comprises applying an electrical stimulus to the medial forebrain bundle of the brain of the mammal.
  • the electrical stimulus can comprise an intermittent stimulation.
  • the stimulus can be delivered by an electrode connected to an implanted neurostimulator.
  • the frequency of the electrical stimulus can be from about 100 to about 250 Hz.
  • the current intensity of the electrical stimulus can be about 800 ⁇ A.
  • the intermittent stimulus can comprise a rest period of between about 4 seconds and about 7 seconds subsequent to the electrical stimulus.
  • the intermittent stimulus can cycle continuously.
  • the electrical stimulus can comprise a burst-like stimulation.
  • the burst-like stimulation can comprise an alternating cycle of a 0.2 second current pulse followed by a 0.2 second inter-stimulus rest.
  • the intermittent stimulus can comprise about twenty alternating cycles.
  • this document features a method for treating a human having Parkinson's disease.
  • the method comprises applying an intermittent electrical stimulus to the medial forebrain bundle of the brain of the human.
  • the stimulus can evoke dopamine release in the striatum of the brain, thereby treating the human.
  • the stimulus can be delivered by an electrode connected to an implanted neurostimulator.
  • the frequency of the electrical stimulus can be from about 100 to about 250 Hz.
  • the current intensity of the electrical stimulus can be about 800 ⁇ A.
  • the intermittent stimulus can comprise a rest period of between about 4 seconds and about 7 seconds subsequent to the electrical stimulus.
  • the intermittent stimulus can cycle continuously.
  • the electrical stimulus can comprise a burst-like stimulation.
  • the burst-like stimulation can comprise an alternating cycle of a 0.2 second current pulse followed by a 0.2 second inter-stimulus rest.
  • the intermittent stimulus can comprise about twenty alternating cycles.
  • Figure 1 Schematic of an experimental set-up to amperometrically record dopamine release in the striatum evoked by electrical stimulation of dopamine axons contained within the medial forebrain bundle (MFB).
  • SN refers to the substantia nigra, the site of origin of dopamine neurons in the midbrain.
  • FIG. 1 Electrical stimulation parameters applied to the medial forebrain bundle for each of the four groups of mice.
  • Each of the test stimulation groups consisted of 300 pulses, with Groups 1 and 3 (Gl and G3) having equal stimulation off periods and Groups 2 and 3 (G2 and G3) having equal stimulation on periods.
  • Group 4 (G4) consisted of a continuous train of electrical stimulation applied at 100 pulses per second.
  • the 300 pulses were applied in a burst fashion with 20 pulses at a time applied over a 0.2-second period, which is equivalent to 100 pulses per second for each burst.
  • MFB medial forebrain bundle
  • Figure 4 Changes in striatal dopamine oxidation current in picoAmps (pAmps; 10 ⁇ 12 Amps) during the first 100 seconds of electrical stimulation of the medial forebrain bundle for representative mice taken from Groups 1-4 (Gl -4; black line in each panel).
  • Figure 5. Steady-state levels of dopamine oxidation current (pAmps; 10 "12
  • Figure 8 Tabulation of the average overall levels of striatal dopamine release evoked by stimulation of the medial forebrain bundle for each of the test stimulation parameters, and control parameter.
  • Figure 9. Multiple t-test analysis between Groups 1 and 2 average value of summed dopamine oxidation current (p ⁇ 0.0001).
  • FIG. 15 A representative coronal MRI and corresponding fiducials (white circles) on the MRI-compatible head frame for pre -operative planning and calculation of the trajectory coordinates (dark line) for implantation of a DBS electrode in the STN of the pig.
  • B. Expanded view of the pre-operatively planned trajectory for implantation of a DBS electrode in the STN.
  • C. A representative coronal MRI for pre-operative planning and calculation of the trajectory coordinates (dark line) for implantation of a carbon-fiber recording electrode in the caudate of the pig.
  • D. A coronal MRI showing the post-operative confirmation of the DBS electrode placement in the STN of the pig shown in (A).
  • Figure 16 In vivo characteristics of dopamine release recorded in pig "A" striatum during 2-sec (dark bar) STN stimulation with 5 V at 120 Hz.
  • a cyclic voltammogram recorded at the peak of the evoked increase in dopamine release characteristic of dopamine oxidation (ox.) and reduction (rd.) of the electro formed dopamine ortho-quinone (DOQ) back to dopamine.
  • B. Pseudo-color plot obtained during (dark bar) and after 2-sec STN stimulation with 5 V at 120Hz.
  • FIG. 17 In vivo characteristics of dopamine release recorded in pig "A" striatum during 2-sec (black bar) STN stimulation with 3 to 7 V at 120 Hz. Right panel shows representative pseudo-color plots obtain immediately prior to, during (black bars), and after 2-sec STN stimulation with 3, 4, 5, and 7 V at 120Hz.
  • C. STN stimulation frequency-dependent (60 to 240 Hz at 3 V) increases in dopamine release from pig "A” and pig "D".
  • This document relates to methods and materials involved in treating neuropsychiatric diseases.
  • methods and materials for treating Parkinson's disease (PD) using deep brain stimulation are provided.
  • burst- like stimulation can be delivered to the medial forebrain bundle (MFB) of the brain of a Parkinson's patient, to treat tremor and other motor symptoms.
  • MFB medial forebrain bundle
  • a medical device capable of delivering deep brain electrical stimulation e.g., a neurostimulator such as a MedtronicTM Soletra or Kinetra
  • a lead (or electrode) of a neurostimulator can be positioned in the subthalamic nuclei (STN) of the brain, to provide deep brain stimulation.
  • a battery powered neurostimulator can be implanted (e.g. in the patient's chest) and have an extension connecting the neurostimulator and a lead in the patient's brain.
  • a neurostimulator lead can be positioned in a suitable part of the brain for stimulation-evoked dopamine release.
  • the lead can be positioned to stimulate the medial forebrain bundle directly rather than the STN.
  • Stimulation of the glutamatergic innervations originating from the subthalamic nucleus and terminating in the substantia nigra can activate nigrostriatal dopaminergic neurons directly (e.g., Meltzer et al., "Modulation of dopamine neuronal activity by glutamate receptor subtypes," Neurosci Biobehav Rev. , 21 : 511-518 (1997)).
  • Stimulation of glutamatergic neurons in the subthalamic nucleus that project to the pedunculopontine nucleus in the hindbrain can activate nigrostriatal dopaminergic neurons both by the reciprocal excitatory innervation and subsequent activation of the substantia nigra by subthalamic nucleus glutamatergic efferents, and indirectly by activating pedunculopontine cholinergic and glutamatergic inputs to the substantia nigra that act on glutamate ionotropic and metabotropic receptors located on substantia nigra dopaminergic cells (Blaha and Winn, "Modulation of dopamine efflux in the striatum following cholinergic stimulation of the substantia nigra in intact and pedunculopontine tegmental nucleus-lesioned rats," J.
  • the stimulating electrode can be placed within white matter dorsal to the subthalamic nucleus (Saint-Cyr et al, "Localization of clinically effective stimulating electrodes in the human subthalamic nucleus on magnetic resonance imaging," J. Neurosurg., 97: 1152-1166 (2002); Voges et al, "Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson disease: correlation of therapeutic effect with anatomical electrode position," J.
  • a lead can be positioned unilaterally or bilaterally.
  • An appropriate electrical signal can have a frequency of between 90 Hz and
  • an appropriate electrical signal can have a frequency of 100 Hz.
  • the stimulation can be a series of applied electrical current ⁇ e.g. a train).
  • stimulation can include a train with intertrain rest periods.
  • stimulation parameters can include rest periods in which no current is applied.
  • the rest period can be from about 4 seconds to about 7 seconds.
  • an appropriate parameter for an electrical signal can be a burst- like stimulus.
  • a burst-like stimulus can be a stimulus that mimics the natural pattern of dopamine neuronal activity ⁇ e.g., Hyland et al., "Firing modes of midbrain dopamine cells in the freely moving rat," Neuroscience 114:475-492 (2002)).
  • burst-like stimulus can include an alternating cycle of a 0.2 second current pulse and a 0.2 second inter-stimulus rest.
  • the stimulation cycle can last for about 5-6 seconds, or approximately twenty 0.2 second stimuli.
  • the cumulative rest period from the inter-stimulus rests can be between about 2.5 seconds and 3 seconds.
  • Each burst-like stimulus can be followed by a contiguous rest period of about 4 seconds.
  • electrical stimulation including a period of burst- like stimuli and a subsequent contiguous rest period, can cycle continuously.
  • the methods described herein can be used to treat Parkinson's disease and other diseases involving motor disorders.
  • Parkinsonian tremor, essential tremor, or epilepsy can be treated using the methods described herein.
  • the methods described herein can be combined with pharmacological therapies ⁇ e.g., combined with Levodopa for the treatment of Parkinson's disease).
  • Dopamine release in the striatum evoked by electrical stimulation of dopamine axons contained with the medial forebrain bundle can be recorded amperometrically.
  • dopamine levels can be assessed by placing a carbon fiber "dopamine" recording electrode into the striatum.
  • An electrometer can apply an electrical potential (+0.8 V) to the recording electrode via the auxiliary electrode, forcing the oxidation of dopamine at the recording electrode surface. For example, two electrons can be transferred to the recording electrode for each molecule of dopamine oxidized at the surface of the recording electrode.
  • An analog current, constituting dopamine oxidation, is subsequently converted (A/D converter) to a digital signal that can be monitored in real time on a computer screen.
  • a dopamine oxidation current can correspond to a proportional increase in dopamine release in the striatum as a result of MFB stimulation.
  • mice were anesthetized with urethane (1.5 g/kg, i.p.; Sigma-Aldrich, MO, USA) and placed in a stereotaxic (David Kopf, CA, USA) with a mouse head-holder (Stoelting, IL, USA) within a Faraday cage. Body temperature was maintained at 38 ⁇ 0.5 0 C with a temperature-regulated heating pad (TC-1000, CWE Inc., NY, USA).
  • the stimulating electrode tip was positioned within the medial forebrain bundle containing nigrostriatal dopamine axons (coordinates, in mm from bregma and dura: AP -2.1, ML +1.1, DV -4.25 to -4.6) ipsilateral to the dopamine recording electrode positioned in the dorsomedial striatum (coordinates in mm from bregma and dura: AP +1.4, ML +1.0, DV -2.5) (as described in Franklin and Paxinos (1997)).
  • the depths of both the stimulating and recording electrodes were adjusted for each experiment to maximize stimulation-evoked dopamine efflux tested with 15 pulses at 100 Hz applied every 30 seconds. A delay of 10-20 minutes followed to allow the recorded amperometric signal to stabilize before the start of each experiment.
  • mice There were four groups with 4 mice in each group. In each group, the following electrical stimulation parameters were fixed: interpulse interval of 10 mseconds, pulse duration of 0.5 mseconds, current intensity of 800 ⁇ A, and frequency of 100 Hz. There were three sets of stimulation test parameters and a control stimulation parameter, one for each group, followed by a control experiment for each. Continuous electrical stimulation was performed on each mouse after application of a single test parameter.
  • the three sets of test parameters all consisted of the application of trains of 300 pulses applied intermittently over a 10-20 minute period, but differed in terms of pulse train duration, intertrain interval, and interburst interval (off then on period).
  • the three groups (figure 2) and corresponding test parameters, including group 4 (continuous train stimulation) were as follows:
  • Group 1 Pulse train on duration of 0.2 seconds with an intertrain off interval of 0.2 seconds for a total duration of 5.8 seconds followed by an interburst off interval of 4.2 seconds.
  • Group 2 Pulse train on for a total duration of 3 seconds (no intertrain off interval) followed by an interburst off interval of 7 seconds.
  • Group 3 Pulse train on for a total duration of 3 seconds (no intertrain off interval) followed by an interburst off interval of 4.2 seconds.
  • Group 4 Continuous train stimulation.
  • the carbon fibers of the electrochemical recording electrodes were confined within the dorsomedial striatum for all strains of mice, ranging from 1.34 to 1.54 mm anterior to bregma, 1.0 to 1.75 mm lateral to midline, and (shank to tip) 1.75 to 2.5 mm ventral to the cortical surface of the brain (figure 3, Striatum).
  • the pattern and level of change in striatal dopamine oxidation current (dopamine release) recorded during the first 100 seconds of electrical stimulation of the medial forebrain bundle was markedly different for each group.
  • the first bout of burst- like stimulation elicited a relatively lower level of striatal dopamine release (figure 4, Group 1 dark line).
  • evoked dopamine release had increased to levels significantly greater than all the other groups of mice.
  • the highest level of dopamine release evoked by medial forebrain bundle stimulation in Group 1 was attained within 60 seconds of stimulation (7 th bout) and thereafter declined to reach steady-state evoked levels within 200 seconds of stimulation.
  • Group 2 achieved the next highest level of steady-state evoked dopamine release in the striatum and also exhibited a gradual increase in the level of dopamine release with each bout of stimulation (figure 4, Group 2 dark line).
  • the highest level of evoked dopamine release with this stimulation parameter occurred within 40 seconds of stimulation (5 th bout).
  • this peak increase in the level of dopamine release was followed by a more progressive and rapid decay achieving a significantly lower steady-state level of dopamine release within 200 seconds of stimulation.
  • Group 3 Compared to Groups 1 and 2, Group 3 (3 seconds on, 4.2 seconds off) attained a significantly lower steady-state level of evoked striatal dopamine release (figure 4, Group 3 dark line). In addition, this stimulation parameter did not lead to an initial peak increase in dopamine release as was observed in Groups 1 and 2, but rather exhibited only a decline in the height of each evoked response immediately following the first bout of stimulation. This progressive decline was also significantly faster compared to Groups 1 and 2 with a steady-state level of evoked dopamine release attained within 64 seconds of stimulation (10 th bout).
  • Group 4 Compared to all other groups, Group 4 exhibited the lowest steady-state level of evoked striatal dopamine release (figure 4, Group 4 black line). The pattern of dopamine release evoked by a continuous application of 100 Hz pulses led to an immediate exponential decline in the recorded amperometric signal reaching a steady- state level within 200 seconds of stimulation. As Groups 1, 2, and 4 did not attain steady-state levels of evoked dopamine release until after 200 seconds of stimulation (with only Group 3 reaching steady-state within 64 seconds of stimulation), statistical comparisons of significant differences between these groups were conducted on evoked dopamine levels between 250 and 300 seconds of stimulation (50 second bin). These data are described below.
  • Striatal Dopamine Release during the Period of 250-300 Seconds of Burst, Continuous Intermittent, and Continuous Stimulation Figure 5 shows the mean ⁇ SEM steady-state levels of dopamine oxidation current recorded in the striatum during the period of 250 seconds to 300 seconds of medial forebrain bundle stimulation with each of the three test stimulation parameters (Gl : Burst-like; G2: Continuous 3 seconds on, 7 seconds off; and G3: Continuous 3 seconds on, 4.2 seconds off) and control stimulation parameter (G4: Continuous).
  • Gl Burst-like
  • G2 Continuous 3 seconds on, 7 seconds off
  • G3 Continuous 3 seconds on, 4.2 seconds off
  • control stimulation parameter G4: Continuous
  • Group 1 elicited the highest level of steady-state striatal dopamine release, with Group 2 the second highest, followed by Group 3, and Group 4 the lowest level.
  • this group also exhibited relatively higher patterns of release during each bout of stimulation superimposed on the basal increase in dopamine in response to burst-like stimulation (figure 5 Group 1 , dark line (a single bout of stimulation is indicated by a black bar for each of the test stimulation parameters)).
  • continuous application of 300 second pulses at 100 Hz yielded significantly lower patterns of dopamine release for both Group 2 and 3 and correspondingly lower overall levels of dopamine release compared to Group 1 (figure 5 Group 2, Group 3).
  • continuous stimulation at 100 Hz (figure 5 Group 4, black line) exhibited similar patterns of dopamine release as observed in Group 3, but attained a significantly lower overall level of dopamine release.
  • the average (n 4 per group) overall levels of striatal dopamine release evoked by stimulation of the medial forebrain bundle for each of the three test stimulation parameters, and control stimulation parameter, were assessed by summing dopamine oxidation current over the period of 250-300 seconds after electrical stimulation had begun (figures 6-7). Under these conditions, the average (mean ⁇ SEM throughout) value of summed dopamine oxidation current for Group 1 (burst stimulation), Group 2 (3 seconds on, 7 seconds off), Group 3 (3 seconds on, 4.2 seconds off), and Group 4 (continuous) were 79.4 ⁇ 2.8, 46.9 ⁇ 2.1, 36.3 ⁇ 2.1, and 28.7 ⁇ 1.4 nAmps, respectively (figure 8).
  • burst-like stimulation parameters for DBS in the treatment of PD can allow for greater range of dopamine release. More flexibility for the electrical stimulation system can modulate the level of dopamine in the basal ganglia to effectively alleviate symptoms of PD. Burst- like stimulation can evoke the greatest amount of dopamine release both initially and over an extended period of stimulation, compared to all other stimulation parameters.
  • Burst stimulation can also reduce the overall duty cycle of the stimulator, and extend the battery life of the stimulator. For example, if a battery presently lasts for 2.5 years on a continuous stimulation schedule, the increase in battery life using a burst stimulation schedule (i.e. 0.2 seconds on/off train for 5.8 seconds with 4.2 seconds off) can be calculated to result in a battery life of approximately 9.6 years. This would constitute provide a much longer period between surgical replacement of the battery or eliminate the need altogether, for some patients.
  • Example 2 High frequency stimulation of the subthalamic nucleus evokes striatal dopamine release in a large animal model of human DBS neurosurgery
  • electrochemical techniques including fast scan cyclic voltammetry (FSCV), high frequency stimulation (HFS) of the subthalamic nucleus (STN) is capable of evoking striatal dopamine release in the intact rat (Lee et al., Eur. J. Neurosci., 23:1005-1014 (2006) and Covey et al., Monitoring subthalamic nucleus- evoked dopamine release in the striatum using fast-scan cyclic voltammetry in vivo.
  • FSCV fast scan cyclic voltammetry
  • HFS high frequency stimulation
  • STN subthalamic nucleus
  • FSCV carbon-fiber microelectrode
  • results provided herein demonstrate that the magnitude and temporal pattern of dopamine release evoked by STN electrical stimulation in pig was both dependent upon stimulation frequency and intensity. Moreover, maximal dopamine release was obtained with stimulation parameters that are typically used with therapeutic DBS in PD patients.
  • MRI was performed with a General Electric Signa 3.0 T system.
  • the DICOM image data were then transferred to a stereotactic planning computer, and the anterior commissure - posterior commissure line identified on the MR images.
  • COMPASS navigational software MRI data was then merged with a pig atlas (Felix et al., Brain Res. Bull., 49:1-137 (1999)) and stereotactic coordinates for the DBS electrode implantation trajectory defined ( Figure 15A and B).
  • the recording CFM was prepared by aspirating a single carbon-fiber into a glass capillary, pulling to a fine taper on a pipette puller (Model PE-2, Narashige, Tokyo, Japan), and sealing with nonconducting epoxy (Cahill et al., Anafyt. Chem., 68:3180-3186 (1996)).
  • Borosilicate capillaries containing the carbon fiber were pulled by a laser-based micropipette puller (P-2000, Sutter Instrument Co., Navato, CA).
  • FSCV recordings of STN DBS evoked striatal dopamine release were performed using the wireless instantaneous neurotransmitter concentration system (WINCS) as described elsewhere (Bledsoe et al., J. Neurosurg., I l l :712-723 (2009) and Shon et al., Co-monitoring of adenosine and dopamine using the Wireless Instantaneous Neurotransmitter Concentration System (WINCS): proof of principle, J. Neurosurg., E-Pub Ahead of Print (2009)).
  • WINCS wireless instantaneous neurotransmitter concentration system
  • FSCV not only supports sub-sec measurements at a CFM, but additionally provides a chemical signature in the form of a background-subtracted voltammogram to identify the chemical origin of the signal (Robinson et al., Clin. Chem., 49:1763-1773 (2003)).
  • FSCV parameters for dopamine measurements consisted of a -0.4 V rest potential, 1.5 V peak potential, 400 V/s scan rate, and 10 Hz scan application.
  • a 14 mm burr hole was drilled on the contralateral side of the skull to allow the placement of an Ag/ AgCl reference electrode.
  • preoperative MRI data combined with the pig atlas were used to define the trajectory and final stereotactic coordinates for implantation of the CFM electrode into the center of the head of the caudate (striatum; Figure 15C).
  • Post-m vzvo calibrations of the CFMs utilized in each experiment were performed using a flow injection analysis system (Kristensen et al., Analyt. Chem., 58:986-988 (1986) and Bledsoe et al., J. Neurosurg., 111 :712-723 (2009)). Briefly, individual CFMs were placed in a flowing stream of solution in which various concentrations of dopamine (1 to 10 ⁇ M) were injected sequentially over a 10 second period using an electronic loop injector.
  • the flowing solution consisted of buffered physiological saline (150 mM sodium chloride and 25 mM Hepes at a pH 7.4) pumped at a rate of 4 niL/minute across the CFM, positioned in the center of the inflow tubing to a Plexiglas reservoir.
  • An Ag/ AgCl reference electrode was placed in the bottom of the flow cell reservoir immersed in the buffer solution.
  • Injection of each dopamine concentration permitted the establishment of a dopamine calibration curve to assess the relationship between stimulation-evoked increases in dopamine oxidation current and dopamine extracellular concentration.
  • a hand held stimulator Medtronic screener model 3628, Medtronic Inc.
  • the duration of post-stimulation recovery to pre-stimulation baseline levels for 60 to 240 Hz ranged from 4 to 10 sec (data not shown).
  • the results provided herein demonstrate that electrical stimulation of the STN in the large animal (pig) model of DBS surgery elicited a stimulation time-locked increase in striatal dopamine release that was dependent on both stimulation intensity and frequency.
  • stimulation intensity the increase in evoked dopamine release exhibited a sigmoidal pattern in all three pigs tested, attaining a plateau at around 7 V of stimulation with a fixed frequency of 120 Hz.
  • the maximal concentration in extracellular dopamine attained by these applied stimulus intensities exhibited a relatively high degree of variance between animals (1-4 ⁇ M).
  • STN glutamatergic neurons project to dendrites of SNc dopaminergic cells (Albin et al., Trends Neurosci., 12:366-375 (1989) and Kita and Kitai, J. Comp. Neurol., 260:435-452 (1987)), suggesting that STN stimulation evoked increases in dopamine release in the ipsilateral striatum likely results from STN glutamatergic activation of SNc dopaminergic neurons (Lee et al., Eur. J. Neurosci., 23:1005-1014 (2006) and Shimo and Wichmann, Eur. J. Neurosci., 29: 104-113 (2009)).
  • the evoked dopamine release may be due to direct stimulation of dopaminergic fibers of passage which course within the medial forebrain bundle lying immediately dorsal to the STN (Lee et al., Eur. J. Neurosci., 23:1005-1014 (2006)).

Abstract

La présente invention concerne des méthodes et des matériels impliqués dans le traitement de maladies neuropsychiatriques. Par exemple, l'invention concerne des méthodes et des matériels destinés au traitement de la maladie de Parkinson à l'aide de la stimulation cérébrale profonde.
PCT/US2010/020890 2009-01-13 2010-01-13 Traitement de maladies neuropsychiatriques WO2010083208A2 (fr)

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US9841403B2 (en) 2011-07-21 2017-12-12 Mayo Foundation For Medical Education And Research Differentiating analytes detected using fast scan cyclic voltammetry
US10029101B2 (en) 2013-01-09 2018-07-24 Mayo Foundation For Medical Education And Research Systems for the detection and delivery of neurochemical and electrical signals for functional restoration
US11040197B2 (en) 2017-06-22 2021-06-22 Mayo Foundation For Medical Education And Research Voltammetric neurochemical detection in whole blood

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9603522B2 (en) 2009-08-26 2017-03-28 Mayo Foundation For Medical Education And Research Detecting neurochemical or electrical signals within brain tissue
US9841403B2 (en) 2011-07-21 2017-12-12 Mayo Foundation For Medical Education And Research Differentiating analytes detected using fast scan cyclic voltammetry
US10029101B2 (en) 2013-01-09 2018-07-24 Mayo Foundation For Medical Education And Research Systems for the detection and delivery of neurochemical and electrical signals for functional restoration
US10441791B2 (en) 2013-01-09 2019-10-15 Mayo Foundation For Medical Education And Research Systems for the detection and delivery of neurochemical and electrical signals for functional restoration
US11154718B2 (en) 2013-01-09 2021-10-26 Mayo Foundation For Medical Education And Research Feedback loop for stimulating nerve tissue downstream of a damaged or severed nerve
US11040197B2 (en) 2017-06-22 2021-06-22 Mayo Foundation For Medical Education And Research Voltammetric neurochemical detection in whole blood

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