Patent Application: US-201715463205-A

Abstract:
intractable pain is a horrific cause of world - wide suffering . nervous system excitation is a hallmark of intractable pain and lesioning of excited pathways and structures can produce sustained analgesia . this invention shows that red blood cells exposed to changing magnetic fields are disrupted , releasing hemoglobin , and that this effect is related to the dose of the changing magnetic fields . extrapolating these finding to the nervous system , transcranial magnetic lesioning of select areas of the central nervous system , in particular the anterior cingulate cortex or anterior cingulate cortices , can provide relief for patients who suffer devastating intractable pain . the changing magnetic fields are produced by electrical current through a helmholtz coil with a soft iron core . focusing the magnetic fields within a helmholtz coil has advantages over focusing radiation or ultrasound because the brain can be stimulated before lesioning and the intensity of the magnetic fields can be changed according to the gap distance between the coil . in addition magnetic lesioning of tissues other than that within the nervous system may possibly provide “ bloodless ” surgery without exposure to radiation .

Description:
although numerous neural pathways , structures and neurotransmitters contribute to the experience of intractable pain , there are some generally agreed upon fundamental observations : a . lesioning of the spinothalamic tract as performed in cervical cordotomy reliably produces contralateral analgesia . b . stimulation of inhibitory posterior column tracts of the spinal cord produces analgesia and lesions of the posterior columns produce pain . c . stimulation of inhibitory neurons of the motor cortex that project to the somatosensory cortex produces analgesia . ( lima & amp ; fregni , 2008 ) d . surgical interruption of an excitatory midline dorsal column visceral pain pathway produces analgesia . ( goldberg , 2013 ) e . medications such as local anesthetics that block sodium conduction , anticonvulsants that block sodium , potassium and calcium conduction , gabaergic agonists that inhibit neural transmission and opioids that bind to g coupled receptors all have net inhibitory effects on neural transmission . f . pet scans using cerebral blood flow correlate pain with hyperactivity as measured by increased blood flow of intracranial structures . proposition # 2 : focal lesioning of excitatory nociceptive tracts and structures can produce sustained analgesia . a . lesioning excitatory nociceptive tracts is an aggressive therapy that can be effective for those patients who suffer intractable pain . these therapies include cordotomy , rhizotomy , dorsal root entry zone ( drez ) lesioning and lesioning of visceral afferent fibers of the celiac plexus , hypogastric plexus , splanchnic nerves and lumbar and stellate sympathetic ganglion . b . lesioning of the anterior cingulate cortex has produced analgesia for patients suffering from intractable cancer pain , complex regional pain syndrome , thoracic pain , neuropathic pain and low back pain . ( fuchs et al ., 2014 ) proposition # 3 : transcranial magnetic lesioning of neural structures is technically possible . a . previous experience has shown that it is possible to stimulate neurons of the brain with tms . this procedure has been performed safely on thousands of patients for depression with the most serious rare side effect of seizure . ( wassermann , 1998 ) in order to perform the procedure a magnetic field of approximately 1 - 2 tesla is applied to the scalp and an induced electric field is produced in the brain . tms can be focused but usually with loss of intensity . this invention is a not obvious extension of the tms effects on the brain to include selected neurolysis of the brain from a changing transcranial magnetic field . b . increasing frequency of stimulation increases the conductivity of tissues . ( fig1 and 2 ) c . in this invention it was shown that changing magnetic fields can disrupt the integrity of red blood cell membranes by releasing hemoglobin , and that this effect is related to frequency of the magnetic field , strength of the magnetic field and duration of the magnetic field . ( table 2 ) the hemoglobin released from the disrupted red blood cells exposed to a changing magnetic field can be measured in a spectrophotometer . ( robles , chowdhury , & amp ; wax , 2010 ) this discovery can be reasonably extrapolated to destruction of membranes of neural structures and other tissues . d . the predicted magnetic field strength for brain lesioning based on electromagnetic field strength require to disrupt red blood cell membranes is 0 . 02 tesla to 1 . 5 tesla with a square wave conformation . a magnetic field strength of 1 . 5 tesla approaches the maximum obtainable field strength without special cooling of the magnetic coil and without saturation of the soft iron core . e . the conformation of the changing magnetic field would maintain the characteristics of a helmholtz coil . ( fig3 ) the formula for the b field at the mid - plane of the gap between the coils with an air core is : as the gap between the coils decreases the magnetic field at the mid - plane increases . ( fig4 ) this property of the helmholtz coil can be used to focus the magnetic field . unlike radiation and ultrasound technologies in which the energy dissipates from the source to the desired location the magnetic flux density of a helmholtz coil is such that the b field increases with distance from the poles for a gap distances that are at least larger than ½ of the coil radius . it is predicted therefore that unwanted lesioning of tissue in the path of the magnetic field would be less likely with magnetic lesioning than with radiation or ultrasound technologies . f . identification of the focal point within acc is aided with mri imaging and with patient reports of stimulation before lesioning . g . the predicted frequency of the changing magnetic field based on the frequency require to disrupt red cell membranes and conductivity of brain tissue is 100 kilohertz to 1 , 000 kilohertz . h . the predicted duration of the brain tissue exposed to a changing magnetic field based on the duration to disrupt red cell membranes is 10 - 120 minutes . the shortest duration possible would permit the lesioning to occur without movement . i . the predicted pathway of the magnetic field would be skin and subcutaneous tissue , temporalis muscle , frontal bone , lateral and medial portion of the anterior cerebral cortex to the acc or anterior cingulate cortices . the line of this field would not disturb the temporal lobe or major sensory and motor tracts . proposition # 4 : even though specific brain biomarkers of pain have not been elucidated , lesion ( s ) most likely to produce analgesia can be deduced by considering the human experiment data of 1 ) autoradiography of mu receptors in the brain , 2 ) pet scans of location of brain mu receptors and 3 ) cerebral blood flow as measured by fmri activity during experimentally produced pain . ( table 1 ) a . focal lesions of the somatosensory cortices ( s1and s2 ) are rare . literature reviews indicate that these lesions produce anesthesia of the contralateral side but not analgesia . studies suggest that s2 is more concerned with the intensity of the nociceptive stimulus rather than the location of the stimulus . b . motor cortex lesions do not produce analgesia but motor cortex stimulation produces analgesia suggesting that connections between the motor and sensory cortex are inhibitory . c . lesions of the acc can produce analgesia that is not somatotopically specific . the preferred embodiment of this invention based on results from cingulotomy would be to lesion the acc or anterior cingulate cortices . intractable pain causes horrific suffering . those suffering have minimal quality of life . this invention provides a method to decrease pain with non - invasive lesioning of the cns without radiation . in addition it provides a method to perform focal non - invasive lesioning of tissues beyond that of the central nervous system and potential “ bloodless ” surgery . a solution of 50 ml of phosphate buffered saline , 1000 units of porcine heparin and 0 . 5 mg of dextrose was the standard nutrient solution . 10 microliters of blood were obtained from a finger stick and mixed with 20 microliters of nutrient solution in a micro centrifuge tube . 500 microliters of phosphate buffered saline ( pbs ) was added to each micro centrifuge tube . the suspended cells were exposed to changing magnetic fields of variable frequencies , durations and strengths within a helmholtz coil . the micro centrifuge tubes were insulated and temperature measurements within the coil showed no appreciable changes compared to the ambient temperature . this observation excluded temperature effects on red blood cell viability . the helmholtz coil consisted of two solenoids each with 480 turns of wire with a radius of 2 . 5 cm and ½ inch soft iron core . the field is nearly uniform at a distance 1 radius from the inner pole . the frequencies of the magnetic field were produce by an arbitrary wave form generator ( owan model ag 1012f , fujian , china ) and amplified by ( model ts 250 - 1 function generator amplifier , accel instruments , irvine , calif .). additionally the amplifier &# 39 ; s output was monitored with an oscilloscope and a gauss meter measured the magnetic field . after exposure to the changing magnetic fields the red blood cells and controls were centrifuged at 1500 rpm for 5 minutes to produce a red blood cell pellet and supernatant . 400 microliters of supernatant with pbs were assayed in a spectrophotometer ( ultrospec iii , pharmacia , cambridge , england ) at 541 nm for hemoglobin absorption . ( kahn , watkins , & amp ; bermes , 1981 ) the 541 wavelength was determined by best fit beer &# 39 ; s law plot at a peak absorbance . this corresponded to reported absorbance for oxy - hemoglobin and it was felt that conversion to cyano - hemoglobin was not needed for the assay . realizing that the differences in hemoglobin absorbance may be very small between the experimental sample exposed to a changing magnetic field and controls , sample quartz cuvettes were perfectly matched to absorbance values of 3 decimal places between each experiment and the spectrophotometer was recently calibrated . an increase in hemoglobin absorption ( abs ) was observed in the sample group exposed to the changing magnetic field compare to the control samples . 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