Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
  • A61H1/00—Apparatus for passive exercising; Vibrating apparatus; Chiropractic devices, e.g. body impacting devices, external devices for briefly extending or aligning unbroken bones
  • A61H1/02—Stretching or bending or torsioning apparatus for exercising
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
  • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
  • A61H2201/12—Driving means
  • A61H2201/1207—Driving means with electric or magnetic drive
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
  • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
  • A61H2201/12—Driving means
  • A61H2201/1253—Driving means driven by a human being, e.g. hand driven
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
  • A61H2205/00—Devices for specific parts of the body
  • A61H2205/02—Head
  • A61H2205/026—Mandible

Definitions

• the present invention relates to a device for treating or preventing cardiovascular diseases, arterial hypertension, cerebral diseases, cerebral stroke, neurodegenerative diseases.
• the trigeminal nerve is the fifth of the cranial nerves, and it conveys most of sensory information coming from the skull, from the face, from the oral cavity, from the conjunctiva and from the dura mater and provides motor innervation to the jaw muscles.
• the trigeminal system comprises fibres that convey sensory information of different modes, that project to different brainstem nuclei .
• the trigeminal system consists of three main branches: the ophthalmic branch, the mandibular branch and the maxillary branch.
• the ophthalmic and maxillary branches are purely sensory nerves, whereas the mandibular branch contains both sensory and motor fibres.
• the three branches exit from the skull through three foramina, known as the superior orbital fissure, the foramen rotundum and the oval foramen.
• the trigeminal nerve is therefore a mixed nerve that is functionally similar to a spinal nerve.
• the central branches of the sensory fibres and the motor axons penetrate into and exit from the brainstem at distinct locations, i.e. at a sensorial root (afferent root) and at a motor root (efferent root) .
• the cellular bodies of most trigeminal sensory fibres are located at the Gasser's ganglion (or semilunar ganglion).
• the skin of the face contains three types of receptors that convey information through the trigeminal nerve: the mechanoreceptors, the thermoreceptors and the nociceptors.
• the trigeminal nerve also innervates most part of the mouth mucosa, two-thirds of the front tongue portion, and the dura mater of the anterior and media cranial fossae.
• the trigeminal nerve also innervates the dental pulp, the gums and the periodontal membrane.
• trigemino-cardiac reflex By stimulating the various sensory branches of the trigeminal nerve, during facial surgery, considerable effects have been remarked on cardiocirculatory parameters.
• the bradicardia response i.e. a pressure blood reduction and apnea, that occurs by stimulating the trigeminal terminations, is called trigemino-cardiac reflex .
• the trigemino- cardiac reflex can cause symptoms such as hypothension, bradicardia and apnea. It has been observed that the trigemino-cardiac reflex is caused by a stimulation at any position of the trigeminal nerve, and that the trigemino-cardiac reflex disappears substantially immediately once the surgery is completed.
• cardiac frequency and pressure blood follow-up has shown a cardiac frequency average decrease ranging from 78 pulsations/minute to 48 pulsations/minute, with a pressure average decrease of 33%.
• the patients are administered atropine, a cholinergic receptor blocker.
• a lowering the cardiac frequency required administering large atropine doses, in order to avoid a cardiocirculatory arrest in order to avoid a cardiocirculatory arrest.
• a device for treating or preventing cerebral diseases, arterial hypertension, cerebral stroke, neurodegenerative diseases comprising a means for causing an alternating hyperextension of the jaw, in order to cause a cyclical extension of the mandibular elevator muscles with a non-invasive proprioceptive stimulation of regions that are innervated by the trigeminal nerve and with a subsequent stimulation of the trigemino-cardiac reflex.
• alternating hyperextension it is meant a succession of alternating mandibular open-close movements, wherein the opening movement has an extent suitable for stretching the elevator muscles. This way, by cyclically repeating such hyperextension, for example for 10/15 minutes, an optimal stimulation is obtained which causes a considerable trigemino-cardiac reflex.
• the means for causing a hyperextension of the jaw may comprise:
• connection portion arranged between the first and the second portions, which is arranged to apply a contrast force upon approaching of said first and second portions .
• connection portion is arranged to maintain the first and the second portions at a rest distance and to allow the first and the second portions to approach each other upon application of a closing force from the rest distance to a maximum closing distance.
• the rest distance corresponds to the distance between the lower wall of the oral cavity and the upper wall of the oral cavity at the height of the inner dental arch of a patient at a maximum mandibular extension.
• a means can be provided for adjusting the rest distance.
• the above described contrast force has a maximum value set between 14N and 25N.
• the above described adjustment means of the rest distance is housed in a handgrip.
• connection portion is made of a resilient material, in particular of steel, such as stainless 301.
• the means for causing a hyperextension of the jaw comprises:
• the above described lamina has a thickness set between 1 mm and 2 mm, advantageously between 1.1 mm and 1.5 mm, for example 1.2 mm.
• the lamina may have a length set between 15 cm and 25 cm.
• the device as above described, may be used for treating or for preventing cerebral diseases .
• the device as above described, can be used for treating or preventing hypertension .
• the device as above described, can be used for treating or preventing cerebral stroke . Furthermore, the device as above described, can be used for treating or preventing neurodegenerative diseases .
• Fig. 1 shows a perspective view of a possible exemplary embodiment of a device, according to the invention, for treating or preventing cerebral diseases, arterial hypertension, cerebral stroke, neurodegenerative diseases;
• Fig. 2 shows the device of Fig. 1 in a perspective elevational side view
• Fig. 3 shows the device of Fig. 1 in a top plan view
• Fig. 4 shows an elevational side view of the device of Fig. 1 in operation conditions
• Fig. 5 shows an elevational front view of the device of Fig. 1 in operation conditions
• Figs. 6 and 7 diagrammatically show perspective views of two possible exemplary embodiments of the device of Fig. 1;
• Figs. 8A to 8C show respective time plots of the artery systolic pressure (SP) , artery diastolic pressure (DP) and cardiac frequency (CF) measured with a sphygmomanometer, in subjects treated with the device of Fig. 1, the asterisk "*" indicates p ⁇ 0.05 between the data B, representative of the basal value, and the corresponding points;
• Figs. 9A to 9C show respective time plots of the data obtained in patients treated with the device of Fig. 1 ( ⁇ ) and in control conditions ( ⁇ ) by sphygmomanometer measurements, the asterisk "*" indicates p ⁇ 0.0001 between corresponding values of the two curves;
• Figs. 10A to IOC show respective time plots of the values of SP, of DP, and of CF obtained in the subject while masticating a chewing-gum (8) and in control conditions ( ⁇ ) by manual sphygmomanometer measurements ;
• Figs. 16A to 16C show time plots of data obtained by the Finapres system, which are representative of CF in control conditions (Fig. 16A) , by applying the device of Fig. 1 (Fig. 16B) and while masticating a chewing-gum (Fig. 16C) , respectively.
• Fig. 17 shows a time plot of the average blood pressure of a subject treated with IM for 5 minutes. Note the oscillatory trend throughout all the observation period, where (*) indicates p ⁇ 0.05;
• Figs. 18A to 18E show a time plot of the diameter (measured in ⁇ ) of arterioles of order 5, 4, 3, 2 and 1, respectively, in mice treated with mandibular hyperextension (IM) for 5 minutes, (*) indicates p ⁇ 0.05;
• Fig. 19 shows a time plot of the percentage deviation from a respective basal trend of the average blood pressure (PAm) and of the diameter of the arteries of order 2 in patients treated with IM for 5 minutes ;
• Fig. 20 shows the deviation of PAm in patients treated with IM for 10 minutes (the asterisk (*) indicates p ⁇ 0.05);
• Figs. 21A to 21E show respective time plots of diameter (measured in ⁇ ) of the arterioles, of order 5, 4, 3, 2 and 1, respectively, in mice treated with IM for 10 minutes;
• Fig. 22 shows the graph of the percentage deviation from the basal trend of the average blood pressure (PAm) and of the diameter of the arteries of order 2 in patients treated with IM for 10 minutes;
• PAm average blood pressure
• Fig. 23 shows a time plot of the deviation of PAm in patients treated with IM for 15 minutes
• Figs. 24A to 24E show respective time plots of diameter (measured in ⁇ ) of the arterioles, respectively of order 5, 4, 3, 2 and 1 in patients treated with IM for 15 minutes;
• Fig. 25 shows a time plot of the percentage deviation from the basal trend of the average blood pressure (PAm) and of the diameter of the arteries of order 2 taken as a representative example in patients treated with jaw hyperextension for 15 minutes;
• PAm average blood pressure
• Figs. 26A to 26E show a time plot of the diameter (measured in ⁇ ) of arterioles of order 5, 4, 3, 2 and 1, respectively, in the control mice.
• a possible embodiment of a device 1 for causing a mouth hyperextension and activating the proprioceptive sensations of the mandibular muscles of a patient 50 comprises a central portion 30 including a "U"-folded metal lamina of about 1-2 mm thickness, for example 1.2 mm.
• device 1 may be also equipped with curved laminar portions 10 and 20 that are adapted to be arranged, in use, at an upper wall 41 and at a lower wall 42 of the oral cavity of a patient 50.
• curved laminar portions 10 and 20 may be connected to central portion 30 through respective step portions 11 and 21. This allows central portion 30 to go beyond dental arches 51 and 52 of patient 50, in order to arrange laminar portions 10 and 20 respectively adjacent to the palate and to the area between the tongue and the lower dental arch of the patient, or directly on the tongue itself, or in the sublingual region.
• the hardness of the metal of which device 1 is made is such that it allows, in use, to stretch the mandibular elevator muscles.
• device 1 may be made of steel, in particular of stainless steel 301, or in another spring steel in order to apply a resilient contrast force that may be set between about 14 N and about 25 N.
• Fig. 6 relates to a unit 200 for adjusting the rest distance and the maximum force opposed by the jaws, comprising for example inside adjustment means of known type, such as screw, lever, or cam adjustment means.
• An electromechanical adjustment means may also be provided operated by a program means, which modifies the rest length and/or the maximum force according to a predetermined program.
• device 1 has a handgrip 15 by which the user holds device 1. Furthermore, a means 13 may be provided for adjusting a rest distance that corresponds to the distance between the lower wall of oral cavity 42 and the upper wall of oral cavity 41 at the height of the inner dental arch of a patient at a maximum mandibular extension.
• CF cardiac frequency
• SP artery systolic pressure
• DP artery diastolic pressure
• test data have been obtained by examining two different groups (group A and group B) of the patients, as described hereafter.
• a Finapres measure tool was used in order to follow the blood pressure by a non-invasive measurement.
• the blood pressure time plot was obtained by means of a finger cuff designed for detecting blood pulsations.
• the pressure time plot has been used for deducing, by means of a suitable filter, the SP, AP and average pressure measured at the brachial artery.
• three electrodes were applied to the patients, one to the left shoulder, another to the right shoulder and a control electrode at the left hip in order to record an electrocardiograph (ECG) .
• ECG electrocardiograph
• Hemodynamic data and the ECG were taken by a specific computer system and stored for successive analysis.
• An automatic digital sphygmomanometer was also used.
• the measuring cuff was applied at the left arm of the patients and maintained there during the whole recording session.
• the hemodynamic parameters of the patients were automatically determined by an automatic inflating/deflating system and by an automatic Fuzzy Logic detection system.
• the range of the pressure detector was 20-280 mmHg and the range of the cardiac frequency was 40- 180 pulsations/minute.
• the measure precision for pressure was 3 mmHg and for pulsations was 5%.
• CF, SP and DP values were determined 5 times, 3-4 minutes from one another, in order to obtain the basal values of the parameters that were taken into account, indicated in the time plots with B.
• Device 1 was then tested for 10 minutes and the hemodynamic parameters were determined by a digital sphygmomanometer with the following timing: upon completion of 10 minutes (T) , and after that at 5 (5'), 15 (15'), 30 (30'), 50 (50') and 80 (80') minutes.
• the patients of group B followed the same procedure as the patients of group A; moreover, they received the cuff of the Finapres system at the middle finger of their right hand, as well as electrodes for recording the ECG graph. Subsequently, a pulsatility function of the finger cuff was activated and the recording started and continued for 30 minutes, whereas the manual recording was continued up to 80 minutes after completion of the treatment. The first 5 minutes of the Finapres recording matched the last 2 manual measurements that were made of the basal values before each treatment.
• the patients of group B performed 4 recording sessions, on distinct and not necessarily consecutive days, during which, randomly, they were subjected to 4 different treatments: no treatment, application of device 1 for 10 minutes, mastication of a chewing-gum for 10 minutes and positioning and biting an ice cream stick between the teeth for 10 minutes.
• a mandibular hyperextension was imposed with device 1 for 10 minutes to the 20 patients belonging both to group A and To the 20 patients, the artery systolic pressure (SP) , the artery diastolic pressure (DP) and the first (basal, B) cardiac frequency (CF) were measured, just after applying device 1 (T) and then after 5, 15, 30, 50 and 80 minutes. The basal values were obtained as above described.
• Fig. 8A a time plot is shown of the artery systolic pressure (SP) .
• SP artery systolic pressure
• Fig. 8B shows a time plot of the artery diastolic pressure (DP) .
• DP artery diastolic pressure
• Fig. 8C a time plot is shown of the cardiac frequency (CF) .
• the symbol "*" indicates p ⁇ 0.05 between B, the basal value, and the corresponding points.
• Fig. 11A shows SP values
• Fig. 11B shows DP values
• Fig. 11C shows CF values.
• device 1 causes a mouth hyperextension, in addition to a mastication movement and an actuation of the exteroceptive sensations of the palate periodontal front portion.
• the tests carried out by- chewing-gum mastication excluded that the trigemino- cardiac reflex is caused by mastication.
• the SP, DP and CF of 9 of the 20 test patients were measured before and after biting an ice cream stick, i.e. a stiff element, between the upper and lower dental arches of the front portion of the mouth. This allowed to stimulate only the exteroceptive sensations of the patients. Even in this case, DP, SP and CF were determined manually.
• the ANOVA test for repeated two-way measures detected statistically significant differences between the time plots obtained with device 1 ( ⁇ ) and the time plots obtained by using the ice cream stick (
• the above described data show a statistically significant SP reduction with respect to basal values starting from 5 minutes after ending the mandibular stretching and up to 80 minutes, and show also statistically significant reduced DP and CF values with respect to the basal values starting from 15 minutes after the treatment, up to 80 minutes.
• the SP, DP and CF decreases are not due to relaxed and calm conditions in which the patients were placed during the trial, since the measurements that were taken in the same conditions, but without applying device 1, did not point out any change of the parameters measured during the whole recording. Furthermore, statistically- different values are obtained if the data obtained with device 1 are compared with the data related to control conditions .
• the SP decrease is observed occurring before the DP and CF decreases. This allows deducing that the mechanisms that cause such effects are different. Actually, it is possible that a more important neuronal recruiting is needed to stimulate the vasomotor centre, which can cause a CF and DP reduction, that would cause the significant reduction observed after 15 minutes after the end of the stretching.
• mice having a body weight of 250-300 g, and randomly divided into the following test groups:
• group I15min mice subject to basal observation for 15 minutes, then to IM for 15 minutes and to post-IM for 80 minutes.
• control group mice subject only to surgical procedure, and to microcirculation observations for 110 minutes.
• a catheter was inserted into the left femoral artery for recording the systemic blood pressure and for arterial blood gas analysis, whereas a catheter was inserted into the left femoral vein for injecting a fluorescent tracer.
• the body temperature of the mouse was monitored and maintained at 37.0 ⁇ 0.5°C through a special heated stereotaxic holder.
• a cut of 1 cm was made in the skin, in order to expose the skull.
• the skin edges were retracted by suture, thus forming a "well" for a perfusion liquid with two ducts, i.e. an introduction duct a discharge duct, in order to allow a flow and an inlet and outlet liquid flux, and to keep the cerebral surface continuously supplied with liquid.
• the craniotomy was performed by removing the bone and cutting the dura mater away, in order to expose the pial vessels .
• the perfusion liquid artificial cerebrospinal liquid (LCS) : 119 mM NaCl , 2.5 mM KCl , 1.3 mM gS0 4 ⁇ 7 H 2 0, 1.0 mM NaH 2 P04, 26.2 mM NaHC0 3 , 2.5 mM CaCl 2 and 11.0 mM glucose
• a gaseous mixture was bubbled, which contained 10% 0 2 , 6% C0 2 and 84% N 2 at pH 7.38 ⁇ 0.02, and the temperature was maintained at 37.0 ⁇ 0.5°C.
• the stimulation of the mandibular branch of the trigeminal nerve was induced by positioning device 1, according to the invention.
• the opening of the mouth of the animal was fixed up to reaching a maximum allowable mandibular extension, beyond which the mandibular muscles would have been fatigued.
• Muscle fatigue was evaluated in preliminary trials where the mice were subjected to different opening ranges of the mouth, and the tension of the mandibular muscles was measured electromiographically .
• the pial vessels were observed by a fluorescence microscopy technique for in vivo and real-time studying the microvascular changes in a specific tissue, in this case the pia mater. Fluorescence microscopy made it possible to obtain very detailed data, be measuring the diameter and the length of each pial arteriol in order to geometrically characterize the micro vascular pial network .
• microvascular measurements were made off-line by a computer system equipped with a specific software.
• the arteriolar pial network was geometrically characterised in basal conditions.
• the diameters and the length of the pial vessels were measured, by the MIP-CNR computerised method (Lapi et al . , 2007) .
• Each observed microcirculation was mapped, by joining together the pictures of the vessels directly taken from the computer in stop- frame conditions.
• the red blood cells speed was measured at a capillary level by a MIP computer system in an observed area of the cranial window of 150x150 ⁇ , and expressed in mm/s.
• PAm average systemic blood pressure
• the data are expressed as ⁇ E.S average.
• the Kolmogorov-Smirnov method was used. Since the data had a normal distribution, the groups were compared by a parametric test (ANOVA and Bonferroni post-hoc test) . The statistical significance was fixed at p ⁇ 0.05.
• vessels of all 5 orders are present in the sample, in different amounts: since order 5 vessels are located peripherally in the cranial window, it was difficult to observe them and therefore they are not present in all the tests, while the order 2 vessels were present in a greater amount.
• Table 1 hereafter shows the total number of the arterioles belonging to the five orders, the diameter and the length of the vessels. The diameter ranges do not overlap (p ⁇ 0.05 [*] , ANOVA and Bonferroni post-hoc).
• PAm systemic blood pressure
• PAm is reduced and reaches after 5 minutes of the IM a value of 99 ⁇ 2.1 mmHg, which is significantly lower than the basal value (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05; variation ratio:10 ⁇ 2%) (Fig. 17) .
• Order 4 arterioles changed from 46.6 ⁇ 1.1 ⁇ in basal conditions to 45.2 ⁇ 0.8 ⁇ , which corresponds 3 ⁇ 1% of the basal value; order 3 arterioles changed from 34.2+1.1 ⁇ in basal conditions to 34.2 ⁇ 1.1 ⁇ , order 2 arterioles changed from 24+0.9 ⁇ in basal conditions to 22.5 ⁇ 0.6 ⁇ and order 1 arterioles changed from 11 ⁇ 0.2 ⁇ in basal conditions to 10.3 ⁇ 0.1 ⁇ , thus showing a reduction of about 6 ⁇ 2% of the basal values for the three last orders (Figs. 18A-18E) .
• the pial arterioles with diameter of order 5 and 4 significantly increased up to 65.5 ⁇ 1.1 ⁇ and to 53.9+ 0.9 ⁇ , respectively (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), which corresponds to a variation ratio, with respect to the basal value, of 15 ⁇ 3% and of 16 ⁇ 3%, respectively.
• the diameters of order 3, 2 and 1 arterioles increased significantly to 42 ⁇ 0.9 ⁇ , to 29.4 ⁇ 0.8 ⁇ and to 13.4 ⁇ 0.1 ⁇ , respectively (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), which corresponded to a variation ratio of 23 ⁇ 4%, 22 ⁇ 4% and 22 ⁇ 4%, respectively.
• Such increased value was maintained up to 45 minutes post-IM, then the arterioles progressively recovered their basal diameter at 80 minutes (Figs. 18A-18E) .
• PAm significantly decreased down to 93.3 ⁇ 2.5 mmHg in the first 5 minutes of the IM, (A OVA and Bonferroni post-hoc test, p ⁇ 0.05), which corresponds to a reduction ratio of 12 ⁇ 3% with respect to the basal values observed in I5min, and in the following 5 minutes, PAm continued decreasing down to the value of 83.7 ⁇ 2.0 mmHg (ANOVA and Bonferroni post- hoc test, p ⁇ 0.05 vs basal), which is 21 ⁇ 2% lower than the basal conditions: such decrease went on for all the post-IM period and at 80 minutes it was still 83.8 ⁇ 2.3 mmHg, which is significantly less than the basal values (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05) (Fig. 20).
• the pial arterioles with diameter of order 5 and 4 were significantly decreased down to 58.8 ⁇ 1.1 ⁇ and to 41.4 ⁇ 1.1 ⁇ , respectively (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), which corresponds in both cases to a variation ratio of 8 ⁇ 3% with respect to the basal values.
• the arterioles with diameters of order 3, 2 and 1 decreased significantly down to 25.4 ⁇ 0.7 ⁇ , 20 ⁇ 0.7 ⁇ and 13.2 ⁇ 0.3 ⁇ , respectively (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), which corresponds to a variation ratio of 18 ⁇ 3%, 19 ⁇ 3% and 20 ⁇ 3% of the basal values, respectively.
• the reduction of the diameter recorded in the first 5 minutes of the IM remained substantially unchanged in the subsequent 5 minutes (Fig. 20) .
• Such a dilation was kept until the end of the observation period, when the diameters were 40.3 ⁇ 0.9 ⁇ (order 3), 32.6 ⁇ 0.6 ⁇ (order 2) and 21.6 ⁇ 0.5 ⁇ (order 1).
• the vasodilatation determined a significant increase of the speed of the red blood cells in the capillary vessels, with respect to the controls. Such speed, calculated at the end of the observation, was 0.35 ⁇ 0.03 mm/s (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05).
• mice treated with IM for 15 minutes after an observation period of 15 minutes in basal conditions have shown in the first 10 minutes of the IM a progressive PAm decrease down to a value of 90 ⁇ 2.1 mmHg, which is significantly less than the basal values (PAm basal: 114 ⁇ 2.5 mmHg; ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), and which was substantially maintained during the following 5 minutes of treatment and all the post-IM period (Fig. 23) .
• the diameters of order 5 arterioles (basal diameter: 60 ⁇ 1 ⁇ ) and order 4 arterioles (basal diameter: 47 ⁇ 0.9 ⁇ ) had a progressive decrease with respect to the basal values, which was significant even after only 5 minutes of IM (57+1.1 ⁇ and 43.3+0.9 ⁇ , respectively, ANOVA and Bonferroni post-hoc test, p ⁇ 0.05), and which was maintained in the following 10 minutes of IM; then, a significant increase followed (ANOVA and Bonferroni post-hoc test, p ⁇ 0.05) that after 5 minutes brought the diameter of the vessels up to 65.7+0.8 ⁇ and to 50.8 ⁇ 0.8 ⁇ , respectively, and after 45 minutes up to 69.4 ⁇ 0.7 ⁇ and 54.5 ⁇ 0.9 ⁇ , respectively.
• PAm significantly decreased, as well as the diameter of the pial arterioles.
• PAm maintained values significantly lower than basal values, and the arterioles shown a remarkable vasodilatation which concerned more significantly order 2 arterioles, as shown in Figs. 24A to 24E.
• Table 2 hereafter shows the fluctuating values of the diameters of the observed vessels of each order.
• IM mandibular hyperextension
• test data were obtained using the mouse pial microcirculation, which represents a valid experimental model for observing in vivo the cerebral blood flow, since it is characterised by surface arterioles, anastomotic arterioles and penetrating arterioles which attain the underlying cortical layer; therefore, the study of these vessels provides an indirect evaluation of the blood flow even at the cortical level . Furthermore, since the cerebral vessels of the mouse have similitude with human, it is possible to obtain test data that may be extended to humans (Lee, 1995) . Normally, the non- invasive imaging methods used for studying in vivo the cerebral flow, such as Laser Doppler and functional magnetic resonance, do not provide the flow value in a predetermined region of the cerebral tissue and do not discriminate between a type of vessel and another.
• the proprioceptive stimulation of the trigeminal nerve causes a significant decrease of the systemic blood pressure and a decrease of the diameter of the pial arterioles during the whole IM treatment, which is more important for lowest order vessels.
• the trend of the pressure diverged from the trend of the variation of the arteriolar diameters and turned out to be strictly related to the duration of the IM.
• the systemic blood pressure showed a three- step trend, characterised by an increase, a decrease, a new increase which lasted until 45 minutes post-IM, and a return to basal values at 80 minutes.
• the diameter changes of the pial arterioles have shown a more regular trend, since the diameters increased until 45 minutes post-I , and then decreased and attained the basal values again, at 80 minutes.
• the response of the cerebral vessels to a reduction of the systemic blood pressure induced by a proprioceptive stimulation of the trigeminal nerve is much more complex than what the regulation mechanisms of the cerebral circle could lead to suppose.
• the initial pressure fall observed during IM causes at first a vasoconstriction and only afterwards a vasodilation.
• vasoconstriction observed during the IM period is probably due to the activation of the trigeminal proprioceptive afferences, with the activation or liberation of vasoconstrictors mediators. It is important to note that, during this period, the systemic blood pressure decreases. It is therefore possible to suppose also that an activation of the baroceptive reflex may take place. Afterwards, during the post-IM period, the decrease of the systemic blood pressure is associated with a vasodilatation of the cerebral arterioles. Such regulation response of the vascular tone could be caused by the liberation of acetylcholine which acts on the vascular endothelium and releases the relaxing factor (EDRF) . The increased blood flow within the vessels could induce endothelial NOS activation, as previously shown by Iadecola et al . (1994).
• nitric oxide once liberated by the endothelial cells, could in turn induce the activation of a soluble guanylate cyclase which would activate the mechanism of cGMP formation in the vascular smooth muscle cells .with a subsequent reduction of calcium fluxes and the relaxation of the smooth muscle.
• device 1 makes it possible to non-invasively prevent or delay the onset of such diseases as hypertension, as well as the risk of cerebral stroke.

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