WO2007007058A1 - Methode et appareil permettant de reguler la pression sanguine - Google Patents

Methode et appareil permettant de reguler la pression sanguine Download PDF

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Publication number
WO2007007058A1
WO2007007058A1 PCT/GB2006/002525 GB2006002525W WO2007007058A1 WO 2007007058 A1 WO2007007058 A1 WO 2007007058A1 GB 2006002525 W GB2006002525 W GB 2006002525W WO 2007007058 A1 WO2007007058 A1 WO 2007007058A1
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WIPO (PCT)
Prior art keywords
stimulation
blood pressure
brain
region
human
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PCT/GB2006/002525
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English (en)
Inventor
Alexander I. Green
John E. Stein
Tipu Z. Aziz
David J. Paterson
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Isis Innovation Limited
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Publication date
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Publication of WO2007007058A1 publication Critical patent/WO2007007058A1/fr

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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
    • A61N1/36—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
    • A61N1/36114—Cardiac control, e.g. by vagal stimulation

Definitions

  • Blood pressure irregularities are a health concern for humans.
  • Currently available methods to adjust irregularities in blood pressure (BP) in a human include diet, exercise, relaxation, lowering of salt intake and prescription drugs.
  • BP blood pressure
  • Such treatments can result in variable outcomes, may be effective for only relatively short periods of time, and maybe less effective in humans with severe blood pressure irregularities.
  • the present invention relates to a method and a device for influencing blood pressure in a human.
  • the invention includes a method of influencing blood pressure in a human, comprising the step of applying a stimulation in a region of a brain in a human in a manner influencing blood pressure.
  • the invention includes a method of influencing blood pressure in a human, comprising the step of applying a stimulation in a region of a brain in a human having a hypotension condition.
  • the invention includes a method of influencing blood pressure in a human, comprising the step of applying a stimulation in a region in a brain in a human having a hypertension condition.
  • the invention includes an apparatus for influencing blood pressure in a human subject, comprising a blood pressure sensor detecting blood pressure; a processor in communication with the blood pressure sensor and generating a control signal based on the blood pressure; a signal generator in communication with the processor generating a stimulation signal based on the control signal; and an electrode including at least two conductors in contact with a region of the brain that stimulates the region as a function of the stimulation signal in a manner influencing blood pressure in a human subject.
  • the invention is an apparatus for stimulating a region in a human brain, comprising a signal generator adapted to generate a signal; and at least one electrode disposed in a region of a brain in a human subject adapted to produce an output as a function of the signal to stimulate the region in a manner influencing blood pressure in the human subject.
  • Another embodiment of the invention is an apparatus for generating a signal for controlling stimulation of a region in a human brain in a human subject, comprising a blood pressure sensor adapted to provide a blood pressure measurement of blood pressure in a human subject; a microprocessor controller in communication with the blood pressure sensor adapted to convert the blood pressure measurement to a control signal that, when received by a signal generator in operative arrangement with electrodes deployed in a region of a brain of the human subject, causes the signal generator to generate a signal that stimulates the region in a manner that influences the blood pressure.
  • the invention described herein provides a method and a device for influencing blood pressure in a human.
  • Advantages of the claimed invention include, for example, treatment of a human with a blood pressure irregularity with a relatively consistent outcome and for an extended period of time, especially in humans with severe blood pressure irregularities or where currently available treatments have failed.
  • blood pressure can be influenced in a human by applying a stimulation in a region of the brain in the human in a manner to influence blood pressure to potentially reverse, adjust, or dimmish an irregularity in blood pressure in a human.
  • FIGs. IA and IB are diagrams of a device, employing the principles of the present invention, using an electrode deployed in a brain of a human subject.
  • Fig. 2 A is a close-up diagram of an embodiment of an aspect of the device of Figs. IA and IB.
  • Fig. 2B is an alternative embodiment of the aspect of the device of Fig. 2 A.
  • Figs. 2C-2E are diagrams of various embodiments of the electrodes used by the aspect of the device of Figs. 2 A and 2B.
  • Fig. 3 is a block diagram of electronics used in the device of Figs. IA and IB.
  • Fig. 4 is a flow diagram of an example process performed by the electronics of Fig. 3.
  • Fig. 5 is a post-operative, axial, Tl -weighted, Magnetic Resonance (MR) scan showing the electrode of Fig. 2 A positioned in the brain. The electrode is in contact with the VPL of the left thalamus (lateral) as distinct from the wire of the more medial and deeper PVG electrode. Insert depicts the ACPC plane.
  • MR Magnetic Resonance
  • Fig. 6 A is an annotated scan indicating saggittal positions of the electrode of Fig. 2A in human subjects in whom there were changes in blood pressure during testing.
  • Fig. 6B is an annotated scan indicating coronal positions of the electrode corresponding to the annotations of Fig. 6A.
  • Patients #1-7 all had reduction in BP (blue contacts) and are the most ventral electrodes. Conversely, #8-11 and the upper 2 electrodes of #1 and #6 had a rise in BP. Gray contacts are those that, when stimulated, had no effect on BP.
  • Fig. 7 A is a plot of an intra-arterial blood pressure recording of a human subject responsive to stimulation by the electrode of Fig. 2A. Both systolic and diastolic blood pressure sustained a rise when the stimulation ("stim") was 10Hz, 120 ⁇ s, 4.Ov.
  • Fig. 7B is a plot of finger arterial pressure measurements (Finapress ® ) at
  • Fig. 8 A shows plots of multiple metrics related to blood pressure averaged across multiple human subjects resulting from stimulation of the electrode of Fig. 2A in a ventral area of a region in the brain.
  • the gray area denotes ⁇ one standard error of the mean.
  • Fig. 8B is an annotated scan of a brain indicating regions of deployment of the electrode of Fig.
  • FIG. 9 A shows plots of multiple metrics related to blood pressure averaged across multiple human subjects resulting from stimulation of the electrode of Fig. 2A in a dorsal area of a region in the brain.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • PP pulse pressure
  • R-R interval maximum dP/dt for the six patients with a rise in BP during stimulation of dorsal PVG (note that two of these are the same patients who also had a reduction in blood pressure). Stimulation was started at 100s and stopped at 400s. The gray area is one standard error of the mean.
  • Fig. 9B is an annotated scan of a brain indicating regions of deployment of the electrode of Fig. 2A corresponding to the plots of Fig. 9A.
  • the image shows the location of the active contacts (squares) and their proximity to the centre of the Red Nucleus (dot). Radial distances are 5, 8 and 1 lmm.
  • SC superior colliculus
  • AC anterior commissure
  • PC posterior commissure.
  • Pink line ACPC plane.
  • Fig. 1OA is a plot of power spectra of Systolic Blood Pressure (SBP) for the human subject in response to stimulation in ventral and dorsal areas of the brain regions of Figs. 8B and 9B, respectively.
  • SBP Systolic Blood Pressure
  • SBP systolic blood pressure
  • Fig. 1OB is a logarithmic histogram indicating changes in SBP for the human subject caused by stimulation of the electrode in ventral and dorsal areas of the brain regions of Figs. 8B and 9B.
  • Figs. 1 IA-I II are plots that illustrate changes in systolic blood pressure (SBP), heart rate (HR), and dP/dt on standing.
  • A-C mean changes in systolic blood pressure for Patient 1 (#1), MOI group (MOI), and non-MOI group, respectively.
  • D- F changes in heart rate for the same groups.
  • G-I changes in dP/dt for the same groups. All traces include the mean of three sessions, averaged every 10 seconds. Gray area, period when patient was sitting; yellow area, period of standing; black line, stimulation off; red line, stimulation on. Error bars show + one standard error of the mean.
  • Figs. 12A-12D include timing diagrams, a scan, and a diagram of an electrode implanted into the PVG and PAG as described in reference to Example 3.
  • Fig. 13 examples of raw ontraoperative data for each patient.
  • Patient #1 and #2 had increases and decreases in arterial blood pressure (ABP), depending on the electrode position.
  • 0-100 and 200-300 seconds resting and recovery periods.
  • 100- 200 seconds PAG stimulation on.
  • Fig. 14 patient #1 - summary of changes.
  • A. Decrease in SBP with stimulation (location 1) was accompanied by a decrease in pulse pressure (PP), diastolic BP (DBP) and dPdt. Although decrease in RR interval was significant, it was a small change.
  • 100-200 seconds stimulation period.
  • Fig. 16 normalised changes in cardiovascular variables with stimulation.
  • the Y axis is a ratio of the variable during 100s of stimulation, versus an equivalent resting period with stimulation off.
  • Fig. 17 post-operative electrode location.
  • A Sagittal view of the midbrain showing the superimposed electrode positions in those patients in whom BP significantly changed with stimulation.
  • the electrode contacts that provided optimum pain relief are coloured and are both those that were studied and those used for chronic stimulation. Contacts that reduced BP are shown in blue, those that increased BP are red. Inset shows the level of the AC-PC line. The orange line indicates the approximate level of the aqueduct and therefore the distinction between ventral and dorsal PAG.
  • B Location of electrodes that had no effect on BP (the contacts used are coloured green).
  • RN red nucleus
  • SC superior colliculus
  • AC anterior commissure
  • PC posterior commissure (with pink line joining the two)
  • PAG periaqueductal grey
  • PVG periventricular grey.
  • Fig. 18 comparison of visual analogue scores with cardiovascular variables.
  • VAS visual analogue score
  • ' SBP systolic blood pressure Fig.
  • Fig. 20 long-term changes in McGiIl Pain Questionnaire (MPQ) scores compared to BP changes.
  • D Similar results for Question 7 which gives a patient the choice of one out of four words that describe 'burning' sensation, in increasing severity (0-4). These results show that those patients who had a decrease in blood pressure obtained the best analgesia over the long-term.
  • Stimulation appears to work particularly well on the burning component of pain, which may have a vascular component.
  • Fig. 21 long-term changes in MPQ scores compared to BP changes.
  • the present invention relates to a method of influencing blood pressure in a human comprising the step of applying a stimulation in a region of a brain in the human in a manner influencing blood pressure and a device to influence the blood pressure in a human.
  • ventral stimulation of a region of the brain e.g., PVG 5
  • dorsal stimulation of a region of the brain e.g., PVG, PAG
  • the stimulation is in a region of the brain (internal to the cranium), not to the skin or cranium.
  • “Influencing blood pressure,” as used herein, refers to a change (e.g., increase, decrease) in blood pressure in a human following stimulation in a region of the brain compared to the blood pressure in the human before stimulation in a region of the brain. For example, by applying a stimulation in a region of the brain of the human, blood pressure in the human can be influenced to increase or decrease compared to the blood pressure in the human before application of the stimulation.
  • a human is also referred to herein as a subject or a patient.
  • the region of the brain that is stimulated includes the periventricular gray (PVG) region of the brain. In another embodiment, the region of the brain that is stimulated includes the periaqueductal gray (PAG) region of the brain.
  • PVG periventricular gray
  • PAG periaqueductal gray
  • the human treated by the methods described herein can have hypotension (e.g., a hypotension condition such as orthostatic hypotension) or hypertension.
  • the human having hypertension or hypotension can further have a pain condition, such as neuropathic pain.
  • the human treated by methods described herein can have a pain condition (e.g., neuropathic pain).
  • Stimulation in a region of the brain includes applying stimulation to a dorsal region of the brain. Ih a particular embodiment, the dorsal region of the PVG region of the brain is stimulated. Stimulation of the dorsal region of the brain (e.g., PVG, PAG) can be associated with a pressor response in the blood pressure of the human.
  • a pressor effect can increase blood pressure in a human.
  • stimulation in a region of the brain includes stimulation of a ventral region of the brain (e.g., PVG, PAG).
  • the ventral region of the PVG region of the brain is stimulated.
  • Stimulation of the ventral region of the brain can be associated with a suppressor response in the blood pressure in the human.
  • a suppressor response (also referenced to herein as a "depressor" response) can decrease blood pressure hi the human.
  • the method of influencing blood pressure in a human comprising stimulation in a region of the brain in a human in a manner mfluencing blood pressure, can further include selecting a human having a blood pressure irregularity.
  • a "blood pressure irregularity,” as used herein, refers to a blood pressure measurement or assessment hi the human that is not within a normal range for that human. Normal ranges for the human can be determined by one of skill in the art and can depend, for example, on the gender, age, environmental factors, general health and other medications and/or treatments the human may be undergoing.
  • the stimulation When stimulation is applied in a region of the brain in a human having a blood pressure irregularity, the stimulation includes correcting the blood pressure irregularity.
  • Correcting the blood pressure irregularity means that the blood pressure of the human is changed (e.g., increased, decreased) from a blood pressure measurement prior to stimulation to a blood pressure measurement after stimulation that deviates from the pre-stimulation value and approaches or is within a blood pressure measurement observed in a human without a blood pressure irregularity.
  • Correction in the blood pressure irregularity in the human can include normalizing the blood pressure in the human.
  • Normalizing the blood pressure in the human refers to an alteration in blood pressure in the human to approach levels observed or expected in a human of, for example, similar age, weight, gender, health history and medication regimen that does not have a blood pressure irregularity.
  • a human having an elevated blood pressure can have a decrease in blood pressure (e.g., to within normal levels, levels observed in a human without a blood pressure irregularity) following stimulation in a region of the brain in a manner influencing blood pressure (e.g., stimulation of the ventral region of the PVG, PAG or both PVG and PAG), thereby correcting the blood pressure irregularity.
  • a decrease in blood pressure e.g., to within normal levels, levels observed in a human without a blood pressure irregularity
  • stimulation in a region of the brain in a manner influencing blood pressure (e.g., stimulation of the ventral region of the PVG, PAG or both PVG and PAG), thereby correcting the blood pressure irregularity.
  • a human having a low blood pressure can have an increase in blood pressure (e.g., to within normal levels) following stimulation in a region of the brain in the human in a manner influencing blood pressure (e.g., stimulation of the dorsal region of the PVG, PAG or both PVG and PAG), thereby correcting the blood pressure irregularity.
  • the method of influencing blood pressure in a human described herein can further include feeding back a metric representative of blood pressure in an automated manner and responsively adjusting the stimulation based on the metric.
  • the method can further include enabling the feedback of a metric representative of a blood pressure in a manual manner and adjusting the stimulation in response to the metric
  • the stimulation employed in a method of stimulation in a region of the brain in the human in a manner to influence blood pressure can include at least one member selected from the group consisting of an electrical stimulation, a magnetic stimulation, an electromagnetic stimulation, a thermal stimulation, and a mechanical stimulation.
  • the method of influencing blood pressure in the human can further include inductively communicating stimulation parameters used for applying the stimulation.
  • the method can also further include powering a system used for applying the stimulation based on the inductive communications.
  • the method of influencing blood pressure in a human comprising applying a stimulation in a region of the brain to influence blood pressure can further include communicating stimulation parameters used for applying the stimulation by at least one member selected from the group consisting of a radio frequency, an electrical signal, and an optical signal.
  • the method of influencing blood pressure in a human can further include disabling the stimulation in a fail-safe manner.
  • the disabling can be performed in an automated manner based on a metric associated with blood pressure or a detected problem applying a stimulation.
  • the disabling of the stimulation can be activated by the human whose blood pressure is being influenced or by another human (e.g., a physician, a caretaker).
  • the stimulation in the region of the human brain can include selectively applying the stimulation to at least one region of the brain.
  • “Selectively applying the stimulation,” as used herein, refers to the stimulation of a particular region of the brain.
  • the particular region of the brain can be one region (e.g., PAG alone, PVG alone) or more than one region (e.g., PAG and PVG) of the brain.
  • the selective application of the stimulation can be employed for a particular effect in influencing blood pressure.
  • stimulation of the ventral region of the brain e.g., PVG, PAG
  • stimulation of the dorsal region of the brain e.g., PVG, PAG
  • can increase blood pressure also referred to herein as pressor effect in blood pressor
  • the method of influencing blood pressure in a human can include applying stimulation to a region of the brain that includes selectively energizing at least one multiple conductor of at least one electrode disbursed within the region.
  • the method can also include applying a stimulation to the region of the brain including selectively energizing multiple conductors of a single electrode having at least two distal conductors positioned in a ventral region of a nuclei and at least two proximal conductors positioned in a ventral region of a nuclei.
  • the method of influencing blood pressure in the human can include applying a stimulation that includes generating a voltage differential between at least two electrodes of between about - 10V and about +10V with a frequency between about 0.1 Hz and about 1 kHz.
  • Hypertension or postural hypotension may be controlled by manipulation of the stimulation of the PVG, PAG or both PVG/PAG.
  • the following is a detailed description of an apparatus that maybe employed to influence blood pressure in a human by applying a stimulation in a region of the brain (e.g. PVG, PAG) in the human in a manner influencing blood pressure.
  • the apparatus may be used in the methods described herein to influence blood pressure, for example, in a human.
  • Figs. IA and IB are macro level views of a human subject 50 in which a device 100 with an electrode 110 is deployed in operative arrangement with a human brain 101 according to the principles of the present invention.
  • the device 100 is referred to herein as a blood pressure regulator 100 when used in connection with treating or otherwise influencing blood pressure 104.
  • Other components associated with the device 100 are similarly referenced, but may be referred to as simply "device" when used for applications other than influencing blood pressure.
  • the human subject 50 may have a blood pressure irregularity, such as hypertension or hypotension.
  • the blood pressure regulator 100 may include brain stimulation components, such as a signal generator 105, electrode 110, and blood pressure sensor 115, distributed on or within the human subject's cranium 102 or body 103 in operative communication with each other.
  • a wrist band 112 that includes the blood pressure sensor 115 with a transmitter 120 may be positioned on an arm 106 of the human subject 50.
  • the transmitter 120 generates inductive communications signals 125 that use conductivity of the human subject's body 103 to conduct the inductive communications signal 125 to a receiver 122 that receives the inductive communications signal 125 for the signal generator 105.
  • the blood pressure regulator 100 may also include a microprocessor controller (not shown), which may allow the blood pressure regulator 100 to operate in an automated manner.
  • the microprocessor controller may be positioned at the signal generator 105 or the blood pressure sensor 115. Further description of such embodiments is provided below in reference to Fig. 3. Continuing to refer to the embodiment of Fig.
  • the signal generator 105 may be positioned at or in the human subject's cranium 102. Based on metrics or other information related to the blood pressure 104 that may be provided by the blood pressure sensor 115 or microprocessor controller by way of a wireless communications transmitter 120 and receiver 122, the signal generator 105 may cause the electrode 110 to stimulate a selected region or nuclei in the brain or brain stem to influence the blood pressure 104 in a manner (i) treating a blood pressure irregularity or (ii) influencing the blood pressure to change in a predictable manner.
  • the blood pressure regulator 100 may, for example, be used to influence a change in blood pressure 104 for purposes other than for treating blood pressure, such as for testing a drug at an elevated or reduced blood pressure level.
  • the signal generator 105 may generate and output a wide range of electrical signals to the electrode 110.
  • the electrical signals may be a combination of some of the following parameters: -10 to +10 volts, 0.1Hz to IKHz, and have a pulsewidth of 1 nsec to 60 minutes. Specific examples of combinations used during testing are presented below in the Exemplifications section.
  • the electrode 110 may stimulate the region or nuclei with at least one of the following outputs in response to the electrical signal: voltage, current, induced magnetic or electromagnetic field, thermal temperature, and so forth.
  • Fig. IB is a diagram of another embodiment of the blood pressure regulator 100 in which the blood pressure sensor 115 is permanently implanted within the human subject's arm 106.
  • a wire or optical fiber 135 is "threaded" through the human subject's body 103 to form a communications path from the sensor 115 to the signal generator 105.
  • the blood pressure sensor 115 may use the wireless transmitter 120 to communicate with the wireless receiver 122 via inductive or RF communications, as described in reference to Fig. IA.
  • Fig. 2A is a side view of the human subject 50 having the device (e.g., blood pressure regulator) 100 influencing at least one physiological condition of the human body 103 or mind through stimulation of a region or nuclei of the brain 101 according to the principles of the present invention.
  • the blood pressure regulator 100 and electrode 110 are, in one embodiment, disposed in the brain 101 or brain stem 202 in a manner adapted to apply stimulation to a region or nuclei in the brain 101 or brain stem 202 associated with influencing the blood pressure 104.
  • the electrode 110 may include two pairs of conductors 215a, 215b (collectively, conductors 215) in this embodiment.
  • a first pair of conductors 215a may be positioned in a ventral area of the PVG 205, and a second pair of conductors 215b may be positioned in a dorsal area of the PVG 205.
  • the conductor pairs 215a, 215b may be energized by the signal generator 110 via a wire 107 with an electrical signal 220 that produces a voltage differential across the conductors of one or both pairs of conductors 215a or 215b.
  • the voltage differential stimulates the PVG 205 in a manner influencing the blood pressure 104, as described in more detail below in reference to Fig. 2B.
  • Fig. 2B is a side view of another embodiment of the device 100 deployed in the human subject 50.
  • the electrode 110 maybe positioned in the PVG 205, PAG 210, or both.
  • the signal generator 105 is illustrated as being disposed in the brain 101; however, it should be understood that the signal generator 105 may be positioned anywhere within the cranium 102 or external from the cranium 102. For example, the signal generator 105 may be positioned beneath skin (not shown) covering the cranium 102. Wire(s) 107 extending into the cranium 102 may connect the signal generator 105 to the electrode(s) 110 to conduct the electrical signal 220 to the electrode(s) 110.
  • the blood pressure regulator 110 may include one, two, or more electrodes 110, which may be determined on a case-by-case basis.
  • Example embodiments include one electrode 110 that is positioned to have its conductors 215 positioned entirely within the PVG 205.
  • a single electrode 110 may be positioned such that the conductors 215 are positioned entirely within the PAG 210.
  • a single electrode 110 may be positioned so that the electrode 110 extends into both the PVG 205 and PAG 210 with its conductors 215a, 215b mechanically disposed in a respective region or nuclei 205, 210 to selectively stimulate one or both regions or nuclei at a time.
  • the electrode(s) 110 may be fixedly positioned ventrally or dorsally within one or both of the nuclei 205, 210.
  • the electrode(s) 110 may be fixedly positioned dorsally in the PVG 205 or PAG 210.
  • the electrode(s) 110 maybe fixedly positioned ventrally in one or both of the nuclei 205, 210.
  • the conductors 215 on the electrode(s) 110 may be activated in a variety of ways through control by the signal generator 105.
  • a first pair of conductors 215a may be positioned in the PVG 205
  • a second pair of electrodes 215b maybe positioned in the PAG 210.
  • a microprocessor controller (discussed below in reference to Fig. 3) may cause the signal generator 105 to activate one or both pairs of conductors 215a, 215b in a manner adjusting the stimulation of the PVG 205 or PAG 210 to optimize blood pressure response to the stimulation.
  • At least one mechanical or electrical switch (not shown) may be used to direct the electrical stimulation to the selected electrode(s) 110.
  • the electrode(s) 110 may be telescoping electrodes such that the conductors 215 on the electrodes 110 may be positioned in the PVG 205 or PAG 210 in a selectable manner by selectively lengthening or shortening the electrode(s) 110, preferably in a remotely controlled manner.
  • a stint (not shown) or other permanent "tunnel" that allows the electrode(s) 110 to telescope and the conductors 215 to provide stimulation to tissues of the PVG 205 or PAG 210 maybe provided to ensure long-term operability of the telescoping feature.
  • Fig. 2C is another embodiment of a deployment of the electrode(s) 110 in a region of the brain 101.
  • one electrode 110 is positioned in the PVG 205 in a ventral-to-dorsal orientation, and a second electrode 110 is positioned in the PAG 210 in a similar orientation.
  • a first pair of conductors 215a is positioned ventrally in their respective nuclei
  • a second pair of conductors 215b are positioned dorsally in their respective nuclei. It should be understood that fewer or more conductors in the "pairs" of conductors 215a, 215b may be provided along the length of the electrode 110.
  • Fig. 2D is an embodiment having a single signal conductor 215c positioned centrally between two reference conductors 215d, 215e positioned at opposite ends of the electrode 110 for stimulating a ventral area or dorsal area, respectively, of the PVG 205.
  • the signal generator 105 may activate one of the reference conductors 215d or 215e by switching electrical or mechanical switches (not shown) to connect the selected reference conductor 215d or 215e to a "ground" reference potential.
  • the signal conductor 215c and selected, grounded, reference conductor 215d or 215e When connected to a ground reference potential, the signal conductor 215c and selected, grounded, reference conductor 215d or 215e establishes a voltage differential between them, which causes current to flow between the signal conductor 215c and selected, grounded, reference conductor 215d or 215e.
  • the voltage differential/current flow causes stimulation in the ventral or dorsal region of the nuclei.
  • the ungrounded reference conductor i.e., electrically "floating" conductor
  • any other number of conductor configurations are possible to optimize efficiency, minimize blood pressure response times, minimize side effects, or otherwise favorably enhance experience for the human subject 50.
  • the signal conductor 215c may be grounded, and the outer two conductors 2l5d, 215e may be selectively energized. Again, it is a voltage differential (or other potential differential) that causes stimulation. Further, in such an embodiment, one conductor 215d maybe energized at a first voltage level, and the other conductor 215e may be energized at a different voltage level to stimulate ventral and dorsal areas of the PVG 205 or PAG 210 at different levels. It should be understood that the "voltage" level(s) maybe steady state, oscillatory, pulsewidth modulated, duty cycle controlled, or employ other non-steady state modulation.
  • Fig. 2E is a rear view of conductor 110 deployment in a region or nuclei
  • This embodiment includes multiple electrodes 110 that may be positioned vertically, horizontally, or otherwise apart from one another.
  • the conductors 215 maybe activated to cause stimulation in tissue between the electrodes 110 in a ventral, dorsal, or other area of the PVG 205 or other region.
  • a multi-dimensional array of electrodes 110 may be formed within one or both of the nuclei 205, 210, subject to physical limitations. It should be understood that deployment of the electrodes 110 can be done in other nuclei or regions of interest.
  • Fig. 3 is a block diagram of the device 100 according to the principles of the present invention.
  • the device 100 or blood pressure regulator 100 may include a microprocessor controller 305, fail-safe unit 315, signal generator 105, and at least one stimulus electrode 110.
  • the blood pressure regulator 100 may also include a blood pressure sensor 115 and, optionally, a human-controlled feedback interface 310.
  • the components 305, 315, 105, 115, 310 maybe analog, digital, or hybrid circuits, and clear distinctions among these components may or may not be clear depending on implementation.
  • the device 100 may be deployed in the human subject 50 in various ways.
  • dashed line zones 305a, 305b, and 305c illustrate different example deployment configurations on or within the human subject 50.
  • the microprocessor controller 305, fail-safe unit 315, signal generator 105, and stimulus electrode(s) 110 i.e., zones 305a and 305b
  • the blood pressure sensor 115 and human- controlled feedback interface 310 are disposed external from the human subject 50.
  • the signal generator 105 and stim ⁇ lus electrode 110 i.e., zone 305a
  • the signal generator 105 receives command signals from the microprocessor controller 305 and optionally fail-safe unit 315 via wireless, wired, or optical signal path(s).
  • all components 105, 110, 115, 305, and 315 i.e., zones 305a, 305b, and 305c) are deployed in the human subject 50.
  • the blood pressure sensor 100 is adapted to automatically detect the blood pressure 104 in the human subject 50.
  • the blood pressure sensor 115 includes a transmitter (Tx) 120 that transmits inductive communications signals 320 to a receiver (Rx) 122 used by the microprocessor controller 305 to receive the inductive communications signals 320.
  • the inductive communications signals 320 may instead be Radio Frequency (RF) signals.
  • the blood pressure sensor 115 communicates with the microprocessor controller 305 via an electrical or fiber optic transport medium 325 via electrical or optical signals 330.
  • the microprocessor controller 305 uses information in the communications 320 or 330 to determine or calculate control signals for applying a stimulation to a region or nuclei (e.g., PVG 205 or PAG 210) of the brain 101.
  • the microprocessor controller 305 may communicate the determined or calculated control signals to the signal generator 105 via a transmitter 120 and receiver 122, respectively.
  • the control signals may be physically communicated between the microprocessor 305 and signal generator 105 via inductive communications path signals 320 through conduction via the body 103 or electrical or fiber optic path 325.
  • the signal generator 105 Responsive to receiving the control signals from the microprocessor controller 305, the signal generator 105 produces an electrical signal 220 and transmits the electrical signal 220 via a wire or other electrically conductive medium 220 to at least one stimulus electrode 110 positioned in the brain 101 in a region or nuclei that influences the blood pressure 104 in the human subject 50 in a manner treating a blood pressure irregularity, for example, or for some other reason.
  • the human-controlled feedback interface 310 is optionally provided as a means for the human subject 50, doctor, technician, or lay person to "dial in" a blood pressure reading to the microprocessor controller 305, fail-safe unit 315, or other component having a use for blood pressure information or other information the human controlled interface 310 is adapted to provide.
  • the interface 310 may optionally allow simple 'increase' or 'decrease' commands to be entered.
  • the only components in the device 100 are the interface 310, signal generator 305, and electrode(s) 110.
  • the interface 310 and signal generator 105 may be an integrated unit accessible externally from the cranium 102 or body 103.
  • the fail-safe unit 315 may receive signals from any number of components of the device 100.
  • the fail-safe unit 315 may include analog or digital circuitry and optionally circuitry for converting between analog and digital formats.
  • the fail-safe unit may have preset or adaptive protocols used to determine when or how to disable or shut-down the device 100 in a manner safest for the human subject 50.
  • Fig. 4 is a flow diagram of a process 400 employed by the blood pressure regulator 100 according to the principles of the present invention. Some steps in the process 400 may be executed in the microprocessor controller 305, and other steps maybe performed by other components or combinations of components, including the microprocessor controller 305, of the blood pressure regulator 100, as suggested above and described below.
  • the process 400 starts (step 405) and initializes (step 410) to begin operation.
  • Initialization can include any number of initialization sequences, such as power-up sequences, verifying processor operational readiness, verifying transmitters and receivers are using the same communications protocol, and so forth.
  • the process 400 continues by checking whether a 'disable' of the blood pressure regulator 100 has been requested (e.g., manually) or a blood pressure regulator 100 failure has been detected (step 415).
  • An example of a failure detection maybe detection of a low power condition, loss of communications, software error, or other error that may interfere with operations of the blood pressure regulator 100. If disable has not been requested and failure has not been detected (step 415), the process 400 measures and feeds back blood pressure (step 420).
  • blood pressure measurement and feedback is performed in an automated manner. In another embodiment, the blood pressure measurement and feedback is performed in a manual manner through use of the human-controlled feedback interface 310.
  • the process 400 continues and determines whether the blood pressure is within a safe operating range (step 425), meaning that a determination is made as to whether it is safe to continue operating the blood pressure regulator 100. For example, if the blood pressure is observed to be outside a given positive or negative threshold from a nominal or normal operating pressure, the blood pressure regulator 100 may determine that it is itself a cause of a blood pressure irregularity due to, for example, a failure or "runaway" condition.
  • the process 400 may determine whether the blood pressure is at a desired pressure (step 430). If the blood pressure is nominal or normal (step 435), the process 400 returns to a step of checking whether a 'disable' has been requested or a blood pressure regulator failure has been detected (step 415). If the process 400 determines that the blood pressure is low, the process 400 stimulates a dorsal region of a nuclei (e.g., PVG 205 or PAG 210) in the brain 101 or brain stem 202 (step 440) to influence a pressor response of the blood pressure in the human subject's body 103. The process 400 thereafter continues operations (step 415). If the blood pressure 104 is determined to be high, the process 400 stimulates a ventral region of the nuclei (step 445) to influence a suppressor response of the blood pressure 104. Thereafter, the process 400 continues operations (step 415).
  • a nuclei e.g., PVG 205 or PAG 210
  • the process 400 disables the blood pressure regulator (step 450). Similarly, if the blood pressure is outside a safe operating range (step 425) as described above, the process 400 disables the blood pressure regulator (step 450). Thereafter, the process 400 determines whether to suspend operations (step 455), optionally based on a number of criteria or as a result of the human subject's triggering of a fail-safe signal (i.e., 'disable'). If operation is not to be suspended, the process 400 initializes the blood pressure regulator 100 (step 400) as a matter of precaution in one embodiment.
  • the process 400 ends (step 460), and the blood pressure regulator 100 is set into a safe operating mode by, for example, disabling the electrodes 110, powering down, or entering a 'safe mode.
  • the process 400 is an example embodiment used for illustration purposes only. Other embodiments within the context of regulating blood pressure may be employed.
  • Some or all of the steps in the process 400 maybe implemented in hardware, firmware, or software. If implemented in software, the software may be (i) stored locally with the microprocessor controller 305 or (ii) stored remotely and downloaded to the microprocessor controller 305 during initialization (step 410). To begin operations in a software implementation, the microprocessor controller 305 loads and executes the software in any manner known in the art.
  • wireless communications signals 320 may include inductive communications signals, Radio Frequency (RF) communications signals, Bluetooth® communications signals, or other forms of wireless communications signals.
  • RF Radio Frequency
  • Bluetooth® communications signals or other forms of wireless communications signals.
  • various protocols can be employed, such as coding, encryption, or other protocols known to improve communications and make the device 100 resistant to communications errors.
  • communications errors may be caused by internal noise sources (e.g., low battery power, noisy amplifiers, poor analog or digital signal(s) isolation, etc.) or external noise sources, such as large electromagnetic fields (e.g., airport metal detectors, car electronics, etc.).
  • the stimulation that may be applied to the region or nuclei may be electrical stimulation, magnetic stimulation, electromagnetic stimulation, mechanical stimulation, thermal stimulation, or combination thereof. Although testing is described herein in reference to electrical stimulation, further studies maybe conducted to ascertain effectivity and operating parameters of these example other forms of stimulation.
  • the blood pressure regulator 100 is described hereinabove as using a manual feedback system or an automatic feedback system. In the case of the manual feedback system, it should be understood that the blood pressure regulator 100 may operate in a "set and forget" mode or provide temporary stimulation while the human subject 50 is operating the human controlled feedback interface 310.
  • the microprocessor controller 305 may calibrate a target 'set point' or nominal blood pressure level for the signal generator electrodes 110 on a one-time, periodic, aperiodic, as-needed basis, or as-requested basis.
  • power is provided to portions of the blood pressure regulator 100 that are disposed inside the human subject 50 through inductive communications.
  • inductive signals are received by the signal generator 105, for example, via the receiver 122 and converted into power that operates the microprocessor 305, memory (not shown), signal generator 105, failsafe unit 315 or other electronics.
  • a power receiver circuit may include a coil, capacitor(s), power regulator, power collection controller, filters, transformers, DC-to-DC converter controller, or other circuits commonly used to convert inductively coupled signals into usable energy for operating circuits and generating signals to cause the electrode(s) 110 to stimulate the regions or nuclei of the brain 102, as described herein.
  • portions of the blood pressure regulator 100 disposed inside the human subject 50 are powered by way of battery or other power generator source, including, for example, fuel cells or the like.
  • power generator source including, for example, fuel cells or the like.
  • access to the power source must be made available for changing or replenishing the power source on a regular or as-needed basis.
  • a blood pressure regulator Although referred to as a "blood pressure regulator,” it should be understood that the device 100 is operable to influence the blood pressure 104 as a blood pressure controller. The difference is that a blood pressure regulator generally maintains a preselected blood pressure and a blood pressure controller can control the blood pressure to be at a selectable level or follow a command trajectory in a dynamic manner.
  • a blood pressure regulator generally maintains a preselected blood pressure and a blood pressure controller can control the blood pressure to be at a selectable level or follow a command trajectory in a dynamic manner.
  • the principles of the present invention are described herein as being used to influence, regulate or control blood pressure, the principles of the present invention can be applied to other physiological applications, such as pain, anxiety, body temperature 'set point, 'and so forth.
  • the electrode(s) can be positioned within other regions or nuclei other than the PVG 205 or PAG 210.
  • the electrodes 110 maybe partially disposed inside the cranium 102 (with conductors 215 positioned as described above) and extending into or through the cranium 102 in a permanent or temporary configuration.
  • Other voltages/frequencies/pulsewidths can be used to stimulate other regions or nuclei.
  • Other electrode embodiments may be used.
  • Other communications techniques between multiple components may be employed.
  • Positioning the electrode(s) or dorsal areas in the selected region(s) or nuclei may be changed to be in upper or lower areas in the selected region(s) or nuclei when applied for treating or influencing physiological functions other than blood pressure or blood pressure but with lesser efficacy.
  • the device 100 maybe used in the human subject 50 or animals for testing, treatment, or research purposes.
  • PAG stimulation influences BP in the cat (see Kabat H, et ⁇ /.Magoun HW, Ranson JW. Electrical stimulation of points in the forebrain and midbrain. The resultant alteration in blood pressure. Archs Neurol 1935; 34:931-955).
  • the PAG is organized into four longitudinal columns (Carrive P, Bandler R, Dampney RA: Somatic and autonomic integration in the midbrain of the unanesthetized decerebrate cat: a distinctive pattern evoked by excitation of neurones in the subtentorial portion of the midbrain periaqueductal grey.
  • Carrive P, Bandler R Control of extracranial and hindlirrib blood flow by the midbrain periaqueductal grey of the cat. Exp Brain Res 1991 ;84:599-606).
  • Stimulation of the dorsomedial and dorsolateral columns produces an increase in BP whereas stimulation of the lateral and ventrolateral columns produces hypotension and freezing behavior
  • Abrahams VC, Hilton SM, Zbrozyna A Active muscle vasodilatation produced by stimulation of the brain stem: its significance in the defense reaction. J Physiol 1960;154:491-513; see also Duggan AW, Morton CR: Periaqueductal grey stimulation: an association between selective inhibition of dorsal horn neurones and changes in peripheral circulation. Pain 1983; 15:237-48, Lovick TA: Inhibitory modulation of the cardiovascular defense response by the ventrolateral periaqueductal grey matter in rats.
  • ventral stimulation at 10Hz can have a consistent depressor (also referred to herein as "suppressed") response, whereas dorsal stimulation can have a pressor response.
  • depressor also referred to herein as "suppressed”
  • dorsal stimulation can have a pressor response.
  • this study has found corresponding analogous changes in DBP, pulse pressure, and maximum dP/dt (although change in the latter was only weakly significant with respect to fall in BP), but no change in RR interval.
  • the changes may be elicited by a mixture of increased/decreased myocardial contractility (change in dP/dt) and a change in total peripheral resistance (changes in pulse pressure).
  • the changes may be due to an altered sympathetic activity, with little or no change in parasympathetic activity.
  • Afferents to brain stem nuclei (brain stem raphe, nucleus reticularis pontis caudalis and nucleus gigantocellularis) in the rat as demonstrated by microiontophoretically applied horseradish peroxidase. Brain Res 1978; 144: 257-275) and PAG neurones are excited antidromically by NRM stimulation (Shah Y, Dostrovsky JO. Electrophysiological evidence for a projection of the periaqueductal gray matter to nucleus raphe magnus in cat and rat. Brain Res 1980; 193: 534-538). PAG also sends collaterals to the rostroventrolateral medulla (RVLM) (Hudson PM, Lumb BM.
  • RVLM rostroventrolateral medulla
  • Neurons in the midbrain periaqueductal grey send collateral projections to nucleus raphe magnus and the rostral ventrolateral medulla in the rat.
  • Brain Res. 1996 ;733(1):138-41) and serotonin receptor agonists applied to the RVLM produce hypotension (Mandal AK, Zhong P, Kellar KJ, GiIHs R. Ventrolateral medulla: an important site of action for the hypotensive effect of drugs that activate serotonin-1 A receptors. J Cardiovasc Pharmacol 1990; 15: S49- 60).
  • Cardiovascular responses to electrical stimulation of the periventricular/periaqueductal gray were measured in fifteen awake human subjects following routine implantation of deep brain stimulating electrodes for treatment of chronic pain. Stimulation parameters were manipulated under controlled conditions and blood pressure measurements were made with a finger plethysmograph and confirmed with an intraoperative recording. Six controls were also investigated. Heart rate, rate of change of blood pressure and power spectra were calculated.
  • Deep Brain Stimulation of the human PVG/PAG can modulate blood pressure in awake humans. The effect is site specific and related to frequency of stimulation.
  • Control of arterial blood pressure is a complex process that is influenced by both hormonal and neural pathways from the forebrain down to each individual cardiac and vascular myocyte.
  • the periaqueductal gray projects to all medullary regions that control blood pressure (BP) and heart rate, as well as having reciprocal connections with higher centers (Shipley, M. T., Ennis M. Rivzi T. A., Behbehani M. M. Topographical specificity of forebrain in the periaqueductal grey and inputs to the midbrain periaqueductal grey: Evidence for discrete longitudinally organised input columns. In: Depaulis, A. BandlerR.
  • the neurocircuitry of the PAG may play a pivotal role in cardiovascular control, probably via the medulla.
  • the periventricular gray is the most medial of the three regions of the hypothalamus, located adjacent to the third ventricle. This is continuous with the PAG that encircles the cerebral aqueduct. These nuclei have long been known to have an important role in the modulation of pain (Magoun, H. W. Atlas D. Ingersoll E. H. Ranson S. W. Associated facial, vocal and respiratory components of emotional expression: An experimental study. J Neurol Psychopath 17, 241-155; Melzack R, Stotler WA, Livingston WK. Effects of discrete brainstem lesions in cats on perception of noxious stimulation. J Neurophysiol 1958;21:353-67).
  • stimulation of this area in humans can produce fear (Nashold BS Jr, Wilson WP, Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg 1969;30: 14-24) and in animals may increase or decrease blood pressure (Kabat H, Magoun HW, Ranson JW. Electrical stimulation of points in the forebrain and midbrain. The resultant alteration in blood pressure. Archs Neurol 1935; 34:931-955; Abrahams VC, Hilton SM, Zbrozyna A: Active muscle vasodilatation produced by stimulation of the brain stem: its significance in the defense reaction.
  • the patient demographics are summarized in Table I. Fifteen patients (twelve male, three female) were referred for deep brain stimulation for neuropathic pain. Mean age was 51.3 years (range 30-74 years). Four patients acted as their own controls as they had both PVG/PAG and thalamic stimulators. Two controls were patients with non-pain conditions - one with a thalamic deep brain stimulator, the other with a spinal cord stimulator. Informed consent for participation in the study was obtained from each patient, and the study was approved by the local ethics committee.
  • the intended target for placing the deepest electrode contact was marked at the PAG at a level of ⁇ 10mm below the AC-PC line; between the dorsal part of the red nucleus and the superior colliculus in the AP plane; and approximately 5mm lateral to the lateral boundary of the aqueduct and the third ventricle.
  • the electrode trajectory was selected to avoid possible penetration of the surface vessels on the cortex and the lateral ventricle. This leads to some adjustment of the target localization for each individual patient, and likely contributes to inter-patient variation in electrode placement.
  • RadionicsTM electrode of 1.8 mm diameter and 2.0 mm exposed tip was slowly passed towards the target while the impedance values were monitored for a sudden drop in impedance value from 500 - 600? to under a few tens of ohms, suggesting possible penetration of a ventricle.
  • the RadionicsTM electrode was replaced by a Medtronic 3387® electrode (Medtronic Inc., Minneapolis, USA).
  • Test stimuli were applied at ⁇ 3.0V in amplitude, 120 ⁇ s in pulse width and 10 - 50Hz in frequency to check for a warm feeling or paraesthesiae in the area of pain or pain suppression and abnormal eye movements. Once the pain suppression area was identified functionally, the DBS electrode was fixed onto the skull and externalized for further investigation. The whole stimulation system was then internalized a few days later in a second procedure.
  • Electrodes were plotted on a brain atlas (Mai J. K, Assheuer J,
  • the angles of the electrode to the midline and AC-PC line, respectively, were calculated.
  • the relative position of the lowest contact to the posterior wall of the superior colliculus was verified, as was the relative position of the upper electrode to the mid- commissural point.
  • the relative positions of the electrodes from all patients were compared, to rule out inconsistencies among the groups.
  • the non-invasive continuous finger arterial pressure was measured with an Ohmeda Finapres 2300 (FinapresTM, BOC Healthcare, USA).
  • the blood pressure was calibrated using a sphygmomanometer, and the pressure transducer and finger cuff were positioned at heart level during the experiment.
  • Automatic BP measurements from the upper arm were also made every three minutes or when a change in BP was observed (Omron 705CP-II Automatic Blood Pressure Monitor, Omron® Healthcare Europe B.V, Hoofdorp, Netherlands) in order to corroborate the finger arterial pressure measurements.
  • Lead H electrocardiogram ECG was recorded using disposable adhesive
  • Ag/AgCl electrodes H27P, Kendall-LTP, MA, USA
  • amplified* 1,000 CED 1902, Cambridge Electronic Design, Cambridge, UK
  • the finger pressure and ECG were digitized at 4kHz with 16-bit resolution (CED 1401 Mark II, Cambridge Electronic Design, Cambridge, UK) using Spike II software® (version 5.0, Cambridge Electronic Design, Cambridge, UK).
  • an intra-arterial catheter (BD AngiocathTM, Infusion Therapy Systems Inc, Sandy, Utah) was inserted into the radial artery during general anesthesia.
  • the patient was induced with a sleep dose of propofol, and anesthesia was maintained with nitrous oxide in oxygen, midazolam, end tidal concentration sevoflurane 0.5-1% and fentanyl.
  • the arterial pressure signal was transduced using a Medex Medical® transducer and recorded from the anesthetic machine (AS/3® Datex-Ohmeda inc., Tewksbury, MA), sampled at 500Hz with 12-bitresolution (MP 100®, Biopac Systems, Santa Barbara, Ca) using Acqknowledge® software (version 3.7.3, Biopac systems).
  • the dorsal PVG was stimulated at 10Hz at 4.Ov (pulse width 120 ⁇ s) for 3 minutes. This was repeated three times with five minutes rest in-between to confirm the effect.
  • the experiments were started with the patient sitting for 5 minutes.
  • the first session consisted of a 12-minute rest period (while recording cardiovascular variables) with the stimulator turned off. The same procedure was then repeated with the stimulator turned on and randomly set at different settings. If there was a change in BP, stimulation was stopped 300s after it had been started to look at the recovery phase. If there was no change, stimulation was continued for 12 minutes to confirm that there was no effect. There was a 9-minute rest period with the stimulation off in-between each session. This rest period was extended if blood pressure had not yet returned to the baseline value of session 1.
  • the Medtronic 3387® electrode consists of four circumferential contacts measuring 1.5mm, spaced by lmm.
  • bipolar stimulation was used between the two deepest or the two most proximal contacts, at either 10 or 50Hz.
  • the pulse width was 120 ⁇ s and amplitude was increased to the maximum tolerated by the patient, without side effects, up to 3 volts (equivalent to a current magnitude up to 3mA).
  • a typical experiment would consist of at least eight sessions including the rest periods.
  • the session was repeated two further times to confirm the response. Both the patient and the person recording the data were blinded from the actual stimulation parameters. The pain was quantified with a visual analogue score at the beginning and end of each session.
  • FIG. 8A shows the composite data from all seven patients in whom SBP dropped significantly after the onset of stimulation, without significant changes in pain severity (#1 to #7, lower two contacts only in #1 and #6). It is striking that the contacts that reduced BP were the most ventral electrodes (Figs. 6A and 6B, blue electrodes: electrodes 1-6, lower two conductors; electrode 7, upper two conductors). Thus, it appears that stimulation of the ventral PVG/PAG is required to reduce BP. There is considerable variation in the lateral location of electrode placement, which is due to variations in ventricular size that determines intraoperative electrode trajectory, but there does not appear to be a relation to decreased BP.
  • the mean latency i.e., the time from initiation of stimulation to the maximum fall in SBP
  • was 160 ⁇ 29s, although there was a considerable range between subjects (34 to 214 seconds). It is also worth noting that there was a much shorter time between stimulation onset and the initial change in SBP (mean 24 ⁇ 8 seconds).
  • DBP diastolic BP
  • Fig. 1OA shows raw data from one patient
  • Fig. 1OB shows the group data from all seven patients.
  • sympathetic outflow Cohen MA, Taylor JA: Short-term cardiovascular oscillations in man: measuring and modeling the physiologies. J Physiol 2002;542:669-83).
  • Increase of ABP with Stimulation of Dorsal Periventricular Gray
  • the mean latency was 230 ⁇ 44s (with a range of 48 to 289s). As with reduction in BP 5 there was also a much shorter time between stimulation and initial rise in blood pressure of 8 ⁇ 4s.
  • Stimulation parameters required to raise BP were the same as with the episodes of reduced BP (i.e., 10Hz, 120 ⁇ s and up to 3.0v), except that 50Hz did not have the same effect in any patient.
  • mean pulse pressure 11.83 ⁇ 5.4mmHg or 14.5% (pO.Ol, single factor ANOVA)
  • Maximum rise of 17.33mmHg occurred just before 400s.
  • Maximum dP/dt increased by 212 ⁇ 97 mrnHg/s ( ⁇ 0.03, single factor ANOVA).
  • As with reduction in BP 5 there was no significant change in R-R interval.
  • it appears that increasing BP is accompanied by a mirror of the changes that occur during reduction in BP.
  • Patients who had chronic neuropathic pain and who had undergone implantation of a deep brain stimulator in the PVG/PAG were employed. Patients were divided into three groups depending on whether they had orthostatic hypotension (one patient), 'mild orthostatic intolerance' (five patients) or no orthostatic intolerance (five patients). Post-operatively, we continuously recorded blood pressure and heart rate with stimulation off and on and in both sitting and standing positions. From these we derived the blood pressure changing rate (dP/dt). Using autoregressive modelling techniques, we calculated changes in low and high frequency power spectra of heart rate and barorefiex sensitivity. Results
  • Orthostatic Hypotension is a significant clinical problem that affects a large number of people, particularly the elderly (Rutan GH, Hermanson B, BiId DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults.
  • the elderly Rutan GH, Hermanson B, BiId DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults.
  • PAG may project to preganglionic cardiac vagal neurones in the nucleus ambiguus and chemical stimulation of the PAG inhibits baroreflex vagal bradycardia in rats (Inui K, Nosaka S. Target site of inhibition mediated by midbrain periaqueductal gray matter of baroreflex vagal bradycardia. J Neurophysiol 70: 2205-14, 1993.) Stimulation of this area in the human may affect the baroreceptor reflex, hi this study, we investigate the effect of electrical stimulation of this area on postural changes in blood pressure in patients treated for neuropathic pain. A secondary aim was to elucidate the mechanisms of any changes, including autonomic nervous activity and baroreflex sensitivity. These findings will have important implications for the potential use of chronic PVG/PAG stimulation in the treatment of orthostatic hypotension.
  • 'subject #1' had a past clinical history of orthostatic hypotension that resolved after insertion of the stimulator two years previously (the stimulator was constantly on).
  • Etiology of neuropathic pain was as follows; six had suffered thalamic hemorrhage, one a pontine hemorrhage; one brachial plexus trauma; one anaesthesia dolorosa; one post-traumatic headache; one post-craniotomy facial pain. Subjects were divided into three groups depending on the initial change in systolic blood pressure on standing (Table 3); orthostatic hypotension i.e.
  • the intended target for placing the deepest electrode contact was marked at the PAG at a level of ⁇ 10mm below the AC-PC line; between the dorsal part of the red nucleus and the superior colliculus in the AP plane; and approximately 5mm lateral to the lateral boundary of the aqueduct and the third ventricle.
  • the electrode trajectory was selected to avoid possible penetration of the surface vessels on the cortex and the lateral ventricle. This leads to some adjustment of the target localisation for each individual patient, and likely contributes to inter-patient variation in-electrode placement. In patients with post-stroke pain and severely deformed hemispheres, targeting can be quite difficult.
  • RadionicsTM electrode of 1.8 mm diameter and 2.0 mm exposed tip was slowly passed towards the target while the impedance values were monitored for a sudden drop in impedance value from 500 - 600? to under a few tens of? , suggesting possible penetration of a ventricle.
  • the RadionicsTM electrode was replaced by a Medtronic 3387® electrode (Medtronic Inc., Minneapolis, USA).
  • Test stimuli were applied at ⁇ 3.0V in amplitude, 120 ⁇ s in pulse width and 10 - 50Hz in frequency to check for a warm feeling or paraesthesiae in the area of pain or pain suppression, and abnormal eye movements. Once the pain suppression area was identified functionally, the DBS electrode was fixed onto the skull and externalised for further investigation. The whole stimulation system was then internalised a few days later in a second procedure.
  • the Medtronic 3387® electrode consists of 4 circumferential contacts measuring 1.5mm, spaced by lmm. During each session with stimulation on, bipolar stimulation was used between the middle two contacts, at 10Hz.
  • the pulse width was 120 ⁇ s and amplitude was increased to the maximum tolerated by the patient, without side effects, up to 3 volts.
  • the settings used were different to those generally used for pain control, patients were unable to discern whether stimulation was on or off.
  • the session was repeated three times and the average of the three sessions was used. Thus, an experiment consisted of 6 sessions including the rest periods.
  • the non-invasive continuous finger arterial pressure was measured with an Ohmeda Finapres 2300 (FinapresTM, BOC Healthcare, USA).
  • the blood pressure was calibrated using a sphygmomanometer and the pressure transducer and finger cuff (placed on the middle finger) were positioned at heart level during the experiment.
  • Automatic blood pressure measurements from the upper arm were also made every three minutes (Omron 705CP-II Automatic Blood Pressure Monitor, Omron® Healthcare Europe B.V, Hoofdorp, Netherlands) in order to corroborate the finger arterial pressure measurements.
  • ECG Electrocardiogram
  • systolic blood pressure and heart rate were calculated — this was defined as the maximum change from baseline within 30s of standing. Also derived was the percentage change in systolic and diastolic blood pressure, heart rate, pulse pressure, and blood pressure changing rate (dP/dt) at plateau which was defined as the period from 220-28Os.
  • the dP/dt was derived by differentiating the blood pressure. The maximum dP/dt value is the measure of maximum changing of the blood pressure which reflects the contractility of the myocardium.
  • the baroreflex sensitivity index was calculated from the transfer function of systolic blood pressure and RR interval signals using bivariate autoregressive modeling (Barbieri R, Bianchi AM, Triedman JK, Mainardi LT, Cerutti S, Saul JP. Model dependency of multivariate autoregressive spectral analysis. IEEE Eng Med Biol Mag 16: 74-85, 1997, and Zhang Y, Critchley LA, Tarn YH, Tomlinson B. Short-term postural reflexes in diabetic patients with autonomic dysfunction.
  • Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres. Diabetologia 42: 1345-9, 1999), the baroreflex sensitivity was calculated as the average of low and high frequency gains of the transfer function from systolic blood pressure to R-R interval for both sitting and standing positions with stimulation off and on for each patient. This mathematical model essentially compares the effects of changes in systolic blood pressure to changes in heart rate (for both high and low frequencies).
  • the baroreflex sensitivity index would be high i.e. because the baroreflex change is greater, this implies a greater sensitivity of the baroreflex.
  • dP/dt Systolic blood pressure changing rate
  • the resulting decrease in venous return to the heart leads to a compensatory, centrally mediated increase in sympathetic and decrease in parasympathetic activity (i.e., the baroreceptor reflex).
  • This activity usually results in a transient fall in systolic blood pressure of 5 to lOrnmHg, a small rise in diastolic blood pressure (5 to lOmmHg) and a rise in heart rate of 10-25bpm.
  • electrical stimulation of the P VG/P AG reverses or attenuates this fall in blood pressure, and increases the heart rate response to standing in subjects with orthostatic hypotension or intolerance. In a control group of subjects without orthostatic intolerance, the blood pressure changes on standing are unchanged with stimulation.
  • the power of RR interval spectra in the high frequency band (0.15-0.4Hz) has been shown to be a marker of cardiac vagal control (Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 59: 178-93, 1986, and Saul JP, Berger RD, Albrecht P, Stein SP, Chen MH, Cohen RJ. Transfer function analysis of the circulation: unique insights into cardiovascular regulation. Am J Physiol 261: H1231-45, 1991).
  • the low frequency band (0.04-0.15Hz) has been associated with cardiac sympathetic activity, although it has been shown to be affected by both vagal and sympathetic nerves (Berger RD, Saul JP, Cohen RJ. Transfer function analysis of autonomic regulation. I. Canine atrial rate response. Am J Physiol 256: H142-52, 1989, and Saul JP, Berger RD, Albrecht P, Stein SP, Chen MH, Cohen RJ. Transfer function analysis of the circulation: unique insights into cardiovascular regulation. Am J Physiol 261 : H1231-45, 1991). Previous research has shown a reduction in both these components of heart rate variability power with head up tilt in patients with autonomic neuropathy (Zhang Y, Critchley LA, Tarn YH 5 Tomlinson B.
  • Systolic blood pressure changing rate (dP/dt) is a validated measure of cardiac contractility (Brinton TJ, Cotter B, Kailasam MT, Brown DL, Chio SS, O'Connor DT, DeMaria AN. Development and validation of a noninvasive method to determine arterial pressure and vascular compliance. Am J Cardiol 80: 323-30, 1997, and Germano G, Angotti S, Muscolo M, D'Auria F, Giordano M. The (dP/dt)max derived from arterial pulse waveforms during 24 h blood pressure oscillometry recording. Blood Press Monit 3: 213-216, 1998).
  • Pulse pressure is related to peripheral vasoconstriction (Laskey WK, Parker HG Ferrari VA Kussmaul WG Noordergraaf A. Estimation of total systemic arterial compliance in humans. J Appl Physiol 69 (1): 112-9. 1990).
  • Our findings of increased pulse pressure suggest that stimulation increases peripheral vasogenic tone. As this is a sympathetic effect, this adds further evidence that stimulation is acting via an up regulation of the peripheral sympathetic nervous system.
  • the dorsal PAG is known to play a role in regulating the arterial baroreflex (Inui K, Nosaka S. Target site of inhibition mediated by midbrain periaqueductal gray matter of baroreflex vagal bradycardia. J Neurophysiol 70: 2205-14, 1993).
  • the PAG is also linked to the 'exercise pressor reflex' which involves the cardiovascular response to exercise (Iwamoto GA, Wappel SM, Fox GM, Buetow KA, Waldrop TG. Identification of diencephalic and brainstem, cardiorespiratory areas activated during exercise.
  • the NTS receives excitatory convergence of PAG and somatic afferents involved in the baroreceptor reflex (Boscan P, Paton JFR. Excitatory convergence of periaqueductal gray and somatic afferents in the solitary tract nucleus: role for neurokinin 1 receptors. Am J Physiol Integr Comp Physiol 288: R262- R269, 2005). It has also been shown that baroreceptor sensitive neurons in the RVLM can be activated by PAG stimulation (Van Der Plas J, Maes FW, Bohus B. Electrophysiological Analysis of Midbrain Periaqueductal Gray Influence on Cardiovascular Neurons in the Ventrolateral Medulla Oblongata.
  • Deep brain stimulation has been used largely in the treatment of movement disorders, and more recently for depression (Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, Taylor SF, Martis B, Giordani B. Deep brain stimulation for refractory obsessive-compulsive disorder. Biol Psychiatry 57: 510-6, 2005, Bittar RG, Yianni J, Wang S, Liu X, Nandi D, Joint C, Scott R, Bain PG, Gregory R, Stein J, Aziz TZ. Deep brain stimulation for generalised dystonia and spasmodic torticollis.
  • EXAMPLE 3 TREATMENT FOR HYPERTENSION
  • the periaqueductal gray projects to all medullary regions that control blood pressure, as well as having reciprocal connections with higher centers (Shipley, M. T. Ennis M. Rivzi T. A. Behbehani M. M. Topographical specificity of forebrain in the periaqueductal grey and inputs to the midbrain periaqueductal grey: Evidence for discrete longitudinally organised input columns. In: Depaulis, A. Bandler R., eds. The Midbrain Periaqueductal Gray Matter: Functional, Anatomical and Neurochemical Organization. New York, Plenum Press, 1991 :417-448, M'hamed SB, Sequeira H, Poulain P, Bennis M, Roy JC.
  • the electrode was then advanced 3 mm in order to find the position for optimal pain relief. Stimulation at the same parameters had the opposite effect (Fig. 12B) i.e. the blood pressure increased (consistently on three occasions) to a mean of 179 mmHg. Interestingly, in this position, pain relief was not so good. The electrode was therefore withdrawn 3mm before being secured in its final position (Figs 12C, 12D). Stimulation of the thalamic electrode had no effect on blood pressure, although it did provide pain relief.
  • Arterial blood pressure can be increased or decreased by electrically stimulating the periaqueductal gray area in the human[9]. Moreover, the direction of change of blood pressure depends on whether the electrode is in the ventral or dorsal part of the nucleus. Young found that intraoperative blood pressure changes were common with PAG stimulation [10]. This case illustrates that it is possible to reduce blood pressure with electrical stimulation of this area in a hypertensive patient.
  • the medulla contains the major nuclei that control heart rate, blood pressure and respiration.
  • Information from the peripheral arterial and cardiopulmonary baroreceptors and chemoreceptors passes, via the glossopharyngeal and vagus nerves, to the caudal nucleus of the tractus solitarius (NTS)[I I]. From here, impulses are transmitted to the nucleus ambiguous (NA), the dorsal motor nucleus of the vagus nerve (DMNV) and then to the rostral and caudal ventrolateral medulla (RVLM/ CVLM)[12;13].
  • NA nucleus ambiguous
  • DMNV dorsal motor nucleus of the vagus nerve
  • RVLM/ CVLM rostral and caudal ventrolateral medulla
  • the parasympathetic system is activated by the NA and DMNV which contain parasympathetic preganglionic neurones that alter contractility of the heart and heart rate via the vagus.
  • the sympathetic system is activated by the CVLM whose neurones synapse on the sympathetic pre-ganglionic intermediate lateral (IML) neurones that innervate blood vessels and the adrenal medulla and, via catecholamine release, alter the basal tone of blood vessels (Smith JE, Jansen AS, Gilbey MP, Loewy AD. CNS cell groups projecting to sympathetic outflow of tail artery: neural circuits involved in heat loss in the rat. Brain Res 1998; 786: 153-64., and Malhotra V, Kachroo A, Sapru HN.
  • PAG neurones also project to cardiac vagal preganglionic neurones in the nucleus ambiguus, dorsal motor vagal nucleus and the nucleus of the tractus solitarius Farkas E, Jansen AS, Loewy AD. Periaqueductal gray matter projection to vagal preganglionic neurons and the nucleus tractus solitarius. Brain Res 1997; 764: 257-61.
  • the PAG also has reciprocal connections with a number of higher centres. Many of these centres are involved in cardiovascular regulation. Of particular note is the hypothalamus as nearly all its nuclei influence blood pressure and heart rate. Many of the descending connections from hypothalamus pass through and are influenced by PAG.
  • the hypotensive response elicited by lateral hypothalamus stimulation can be attenuated by lidocaine injection into PAG (Pajolla GP, Tavares RF, Pelosi GG, Correa FM. Involvement of the periaqueductal gray in the hypotensive response evoked by L-glutamate microinjection in the lateral hypothalamus of unanesthetized rats.
  • the PAG has direct reciprocal connection with amygdala, prefrontal cortex and insular cortex (Rizvi TA, Ennis M, Behbehani MM, Shipley MT. Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J Comp Neurol 1991; 303: 121-31, and Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 2000; 53: 95-104).
  • the role of PAG in autonomic regulation is probably as an 'integrator' of emotional/ higher influence on cardiovascular control, similar to its role in pain control.
  • hypertension may have important implications for possible future therapies.
  • Refractory hypertension i.e. hypertension that persists despite all available medical therapy, affects approximately 3 % of hypertensive patients (Alderman MH, Budner N, Cohen H, Lamport B, Ooi WL. Prevalence of drug resistant hypertension. Hypertension 1988;11 :II71-5) and can lead to stroke (Almgren T, Persson B, Wilhelmsen L, Rosengren A, Andersson OK. Stroke and coronary heart disease in treated hypertension — a prospective cohort study over three decades.
  • Deep brain stimulation presents a 0.3 % risk of stroke as a direct result of the procedure (this compares to the experience of other groups (Lyons KE, Wilkinson SB, Overman J,Pahwa R. Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures. Neurology 2004;63:612-6). If we are considering this as a treatment to prevent stroke, these risks need to be reduced.
  • deep brain stimulation is an expensive treatment (Yianni J., Green AX, McMosh E,et al. The Costs and Benefits of Deep Brain Stimulation Surgery for Patients with Dystonia: An Initial Exploration. Neuromodulation 2005;8:155-161), particularly in comparison to antihypertensive medication.
  • the defence reaction in the rat is an integrated response that is associated with survival in the wild.
  • the response involves a 'fight or flight' reaction that includes raised blood pressure and heart rate, non-opioid mediated analgesia and emotional effects such as fear McGaraughty, S., Fair, D. A., and Heinricher, M.M.
  • Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala. Brain Res 1009, 223-7 (2004), and Carrive, P. and Bandler, R.
  • periaqueductal gray matter PAG
  • This area is organised into longitudinal columns that are functionally distinct and opposite (Carrive, P., Bandler, R., and Dampney, R. A. Viscerotopic control of regional vascular beds by discrete groups of neurons within the midbrain periaqueductal gray. Brain Res 493, 385-90 (1989).
  • Activation of the dorsomedial and dorsolateral columns evokes the 'fight or flight' response and activation of the lateral and ventrolateral columns produces the passive coping responses described above (Schenberg, L.C. et al. Functional specializations within the tectum defense systems of the rat. Neurosci Biobehav Rev (2005)).
  • Serotonergic and adrenergic sympathetic pathways project to the rostroventromedial medulla (Farkas, E., Jansen, A.S., and Loewy, A.D.
  • the efferent projections of the periaqueductal gray in the rat a Phaseolus vulgaris-leucoagglutinin study.
  • I Ascending projections. J Comp Neurol 351, 568-84 (1995)) the rostroventrolateral medulla, locus coeruleus (Farkas, E., Jansen, A.S., and Loewy, A.D. Periaqueductal gray matter input to cardiac-related sympathetic premotor neurons. Brain Res 792, 179-92 (1998)) and pontobulbar reticular formation (Odeh F, A.M. The projections of the midbrain periaqueductal grey to the pons and medulla oblongata in rats.
  • PAG neurones also project to cardiac vagal preganglionic neurones in the nucleus ambiguus, dorsal motor vagal nucleus and the nucleus of the tractus solitarius (Farkas, E., Jansen, A.S., and Loewy, A.D. Periaqueductal gray matter projection to vagal preganglionic neurons and the nucleus tractus solitarius. Brain Res 764, 257-61 (1997).
  • PAG/ PVG were recruited to the study.
  • Patient demographics are shown in Table 5.
  • AU suffered from chronic neuropathic pain ranging from phantom limb pain to severe orofacial pain of unknown aetiology. Mean age was 49.7 years.
  • One patient (#1) was hypertensive, although poorly controlled, despite polypharmacy. The remaining five patients were normotensive.
  • the study was approved by the local regional ethics committee and informed consent for participation was obtained from all patients.
  • the anterior and posterior commissures were identified on the axial images.
  • the intended target for placing the deepest electrode contact was marked at the PAG at a level of ⁇ 10mm below the AC-PC line; between the dorsal part of the red nucleus and the superior colliculus in the AP plane; and approximately 3mm lateral to the lateral boundary of the aqueduct and the third ventricle.
  • the electrode trajectory was selected to avoid possible penetration of the surface vessels on the cortex and the lateral ventricle. This leads to some adjustment of the target localisation for each individual patient, and likely contributes to inter-patient variation in electrode placement. In patients with post- stroke pain and severely deformed hemispheres, targeting can be quite difficult. For these patients, relative anatomic landmarks such as the third ventricle, the aqueduct, the red nucleus and the superior colliculus are more reliable than AC-PC measurements.
  • the RadionicsTM electrode was replaced by a Medtronic 3387® electrode (Medtronic Inc., Minneapolis, USA).
  • test stimuli ⁇ 5.0V in amplitude, 120 ⁇ s in pulse width and 10 - 50Hz in frequency
  • target i.e. rostral to target
  • This is usually a warm feeling or paraesthesiae in the area of pain or pain suppression, and sometimes abnormal eye movements.
  • the extension leads Medtronic
  • IPG - kinetraTM implantable pulse generator
  • Medtronic implantable pulse generator
  • the GA recordings were performed at the end of this second procedure. As the electrode is fixed, these only involved one target site.
  • the experimental paradigm was as follows; 300s recordings were made; 100s before stimulation, 100s of stimulation at the highest amplitude tolerated (3- 4.5v) followed by 100s after stimulation. This was repeated two more times at each 'target' with 3 minutes of rest (no stimulation) in between each recording.
  • the mean changes in all cardiovascular parameters was taken as the mean of each parameter for the last 30 seconds of stimulation across all three recordings, to take into account any latency of effect.
  • For the GA recordings after 10 minutes of 'rest' at the end of the surgical procedure, three separate three-minute recordings were made with stimulation on, separated by three minutes of stimulation 'off in between.
  • an intra-arterial catheter (BD AngiocathTM, Infusion Therapy Systems Inc, Sandy, Utah) was inserted into the radial artery prior to either the DBS insertion or the implantable pulse generator (IPG) insertion.
  • the arterial pressure signal was transduced using a Medex Medical® transducer and recorded from the anaesthetic machine (AS/3® Datex-
  • the pulse pressure and RR interval were calculated from the measurements of SBP/DBP and ECG respectively.
  • the blood pressure changing rate, dP/dt was derived by differentiating the blood pressure.
  • the maximum dP/dt maximum slope of the blood pressure curve
  • Cardiovascular variables during stimulation were compared to resting periods using one way analysis of variance of BP etc with time (ANOVA).
  • the results represent the average of the changes over three stimulation periods (at each target) for each period. Significance was taken as p ⁇ 0.05. All changes quoted in the results are expressed ⁇ one standard deviation of the mean.
  • Subject #1 and #2 had a significant decrease in ABP when the first (most proximal) location was stimulated, followed by increase in ABP when the second (more caudal) target was stimulated.
  • Subjects #3 and #4 had decrease or increase in
  • the mean change in SBP was a decrease with stimulation from 159.3 ⁇ 2.6 mmHg to 138.9 ⁇ 4.5 mniHg, a decrease of 12.8% (PO.01).
  • This reversed after stimulation rising to 157.8 ⁇ 4.7 mmHg.
  • the RR interval fell with stimulation from 1.14 ⁇ 0.06s to 1.06 ⁇ 0.02s-a fall of 7%-rising again after stimulation to 1.15 ⁇ 0.12s ( ⁇ 0.05).
  • the mean change in SBP was an increase of 7.8% with stimulation from 168.7 ⁇ 1.69 mmHg to 181.9 ⁇ 5.28 mmHg (p ⁇ 0.01). After stimulation it fell, but did not attain the pre-stimulation value (mean 176.6 ⁇ 2.54 mmHg). DBP increased to a lesser extent with stimulation, by 2.9%, from 96.0 ⁇ 1.55 mmHg to 98.9 ⁇ 2.13 mmHg ( ⁇ 0.01). After stimulation DBP fell back to the pre-stimulation value: 95.6 ⁇ 1.76 mmHg. RR interval did not change (1.07 to 1.068s). PP and dP/dt both increased significantly with stimulation (15.4mmHg and 21 OmmHg ⁇ s respectively).
  • BP When the distal location was stimulated (3mm below target), BP consistently increased. SBP increased from 136.3 ⁇ 8.9 mmHg to 162.3 ⁇ 5.6 mmHg, an increase of 19.1% ( ⁇ .001). DBP and dP/dt also significantly increased (35.0%, 45% respectively), but PP did not significantly change. In contrast to most other patients, RR interval decreased significantly with SBP rise, from 0.73 ⁇ 0.01 s to 0.48 ⁇ 0.03 s, representing an increase in pulse rate from 82 bpm to 125 bpm. Power spectral analysis of heart rate showed an increase in Meyer's wave accompanying the rise in ABP. A selection of these results are summarized in Fig. 15.
  • Fig. 16 shows the results (normalised) for the four awake and two anaesthetized patients.
  • changes in SBP were either accompanied by large changes in pulse pressure or RR interval.
  • two out of three patients had large reductions in pulse pressure and reduction in dPdt, with a corresponding decrease in the low frequency component of the power spectrum of heart rate variability (#1 and #2).
  • the third patient (#3) had an increase in RR interval and no change in pulse pressure.
  • the low frequency component reduced, but the high frequency component increased (by 2.82 times - not shown in graph). This increase in the HF:LF ratio is consistent with an increase in parasympathetic activity and is consistent with the increase in RR interval (see discussion).
  • Ventrolateral medullary lesions block the antinociceptive and cardiovascular responses elicited by stimulating the dorsal periaqueductal grey matter in rats. Pain 21, 241-52 (1985)). These cardiovascular changes are part of the 'defence reaction' that an animal uses to improve survival (HUNSPERGER, R. W. [Affective reaction from electric stimulation of brain stem in cats.]. HeIv Physiol Pharmacol Acta 14, 70-92 (1956)).
  • Non-invasive recordings that PAG stimulation can influence blood pressure in humans, see supra.
  • intra-arterial recordings show that stimulation can, in some cases, alter RR interval.
  • the ratio of low frequency: high frequency is important, as this has been shown to be an indicator of the balance between the sympathetic and parasympathetic nervous systems (Accurso V, S. A. S. V. Rhythms, rhymes and reasons - spectral oscillations in neural cardiovascular control. Autonomic Neuroscience: Basic and Clinical 90, 41-46 (2001)).
  • the LF:HF ratio reduced with reduction in blood pressure, implying a greater fall in sympathetic activity.
  • there was actually an increase in HF power despite a fall in LF and fall in SBP. Notably, this was the one patient with a significant increase in RR interval, a change associated with increased parasympathetic activity.
  • EXAMPLE 5 STIMULATING THE HUMAN MIDBRAIN Introduction hi 1884 William James suggested that pain sensations are at least partly due to autonomic reactions changing local blood flow and blood pressure (James W, What is an Emotion? Mind 1884; 9:188-205). Craig (Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3:655-66) has argued that 'interoception' (sensation of the physiological condition of the body) should be defined as the sense of the physiological condition of the entire body, not just the viscera.
  • pain sensitivity defined as the level of stimulus required to produce a subjective feeling of pain
  • blood pressure the opposite of the relationship in pain-free individuals
  • the aim of this study was to correlate blood pressure changes following electrical stimulation of the rostral PAG with changes in the patients' resulting sensations of pain.
  • VAS visual analogue scores
  • MPQ McGiIl Pain Questionnaire
  • non-invasive continuous finger arterial pressure was measured with an Ohmeda Finapres 2300 (BOC Healthcare, USA).
  • the blood pressure was calibrated using a sphygmomanometer and the pressure transducer and finger cuff were positioned at heart level.
  • the finger pressure was digitised at 4kHz with 16-bit resolution (CED 1401 Mark II, Cambridge Electronic Design,
  • each patient completed a McGiIl pain questionnaire (MPQ) on both occasions, in the presence of a specialist nurse.
  • MPQ McGiIl pain questionnaire
  • PRI(R) Ranked Pain Rating Index
  • Melzack Melzack R. The McGiIl Pain Questionnaire: major properties and scoring methods. Pain 1975;l:277-99.
  • PRI(R) Ranked Pain Rating Index
  • Melzack Melzack R. The McGiIl Pain Questionnaire: major properties and scoring methods. Pain 1975;l:277-99
  • Electrode positions were plotted on a brain atlas (Mai et al, 1998) using the post-operative MRI and a manipulation program (MRIcro version 1.38, Chris Rorden).
  • the scan was rotated such that the Anterior and Posterior commissures (AC and PC respectively) were on the same slice.
  • the mid- commissural point was then calculated, followed by the position, in Talairach space, of the electrode contacts.
  • the contacts are visible, circular thickenings in the low signal on the axial scan.
  • the centre of each contact was taken as the position of the electrode and this corresponds to the centre of the contacts in Fig. 17.
  • the angles of the electrode to the midline and AC-PC line, respectively, were calculated.
  • the relative position of the lowest contact to the posterior wall of the superior colliculus was verified, as was the relative position of the upper electrode to the mid-commissural point.
  • the relative positions of the electrodes from all patients were compared, to rule out inconsistencies among the groups.
  • VAS (within one week of surgery) were compared to changes in blood pressure during six 9-minute stimulation periods for each patient (three 'on' and three Off).
  • Fig. 2OD shows that, using a quantitative score of 1 to 4 for the burning component, there was only a significant reduction in the burning component of pain in the decreased BP group, but not the other two.
  • the mean score dropped from 2.3 pre-operatively to 0.4 post-operatively. It therefore appears that there is a relationship between reduced BP and improvement of burning pain.
  • Fig. 17 shows the electrode positions, as determined by the post-operative MRI scans. Note that these are an approximation as every brain is slightly different and there are errors inherent in plotting all electrodes onto one image. We estimate an error of 2-3mm using this technique.
  • electrodes in ventral PAG reduce blood pressure and those in dorsal PAG increase blood pressure (Green et al, 2005).
  • Pain processing in the central nervous system is complex and involves many areas, but there are some areas that have been shown to be important both in pain processing and blood pressure control. These include the nucleus tractus solitarius (this is the first relay station of the baroreceptor afferents), the locus coeruleus and the periaqueductal grey region (Ghione S. Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences.
  • BPV blood pressure variability
  • the 'defence' reaction in the rat is part of an integrated response that aids survival in the wild (Hunsperger, 1956). There are two components to this reaction. Firstly, 'freezing' behaviour that is associated with hypotension, bradycardia, and non-opioid related analgesia and can be induced by ventral PAG stimulation

Abstract

Chez un humain, la pression sanguine est influencée par stimulation d'une région du cerveau. Dans un mode de réalisation, on stimule une région dorsale du cerveau. Dans un autre mode de réalisation, on stimule une région ventrale du cerveau. On utilise un appareil pour stimuler le cerveau d'un humain.
PCT/GB2006/002525 2005-07-07 2006-07-07 Methode et appareil permettant de reguler la pression sanguine WO2007007058A1 (fr)

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