Patent Application: US-31994402-A

Abstract:
the invention is directed to the use of magnetic field designed pulses for the diagnoses and classification of severity of disease states and disability in humans and animals .

Description:
it has now been demonstrated that designed cnps can be used not only for therapeutic treatment of various clinical conditions , but now can also be used for the diagnosis and assessment of a variety of disease conditions some of which are related with pain and / or fatigue and may even be used to diagnose disability as a whole as well as the degree of disability . the use of weak magnetic field pulses to perturb a selected physiological function and recordation of the perturbation for analyses and subsequent disease assessment and diagnoses has not previously been done or suggested . this method has great clinical value in the accurate diagnosis of patients in order to provide for correct and expedient treatment . the present invention has value in the determination of “ real pain ” in a patient rather than “ feigning pain ”. both the medical community as a whole and health insurers may greatly benefit from such technology as it may save a tremendous amount of money that could be put to better use in providing health care to those genuinely in need . the present invention may be used to diagnoses any type of disease state having an impact on motor or cognitive function such as for example but not limited to , parkinson &# 39 ; s , huntington &# 39 ; s chorea , multiple sclerosis ( ms ) and other central nervous system disorders . peripheral disorders such as rheumatoid arthritis , those associated with diabetes and muscular dystrophy may also be diagnosed and assessed using the method of the present invention . the method of the present invention employs a 3 - d helmholtz coil array magnetic field exposure and behavioral monitoring system as is shown in fig1 . this system includes a forceplate , cameras and coil array housed in one room . techron amplifiers and signal conditioners are housed in a separate but attached equipment closet and computers and control / monitoring equipment are housed in a separate but attached lab / office . it is understood that variations to the set up of this system can be made without affecting its integrity or functioning . in the method of the present invention the patient is placed within a volume coil which produces a uniform magnetic field ( cnps ) throughout a specified portion of the patient &# 39 ; s anatomy , such as for example , the head . in the example shown in fig2 the volume coil is sufficiently large that it exposes the entire patient &# 39 ; s body to substantial magnetic fields . however , it is consistent with this amplification that smaller volume coils can be used which would encompass only the head or only a desired extremity . in the method of the invention , specifically designed magnetic field pulses are created such as those described in applicant &# 39 ; s u . s . pat . no . 6 , 234 , 953 . once the patient is placed in the volume coil , the patient is then connected to a physiological readout device . as shown in fig1 this readout device is a 3d forceplate ( or6 - 7 - 1000 , ami , watertown , mass .). it is understood by those skilled in the art that other devices / methods could be just as effective and thus used as a readout device such as for example an eeg array , a squid array or a multi - lead ecg . the important feature for the selected readout device is that it be able to record a physiological phenomenon that is to be perturbed by the magnetic field exposure . for example , the 3d forceplate provides a measure of standing balance that is an outcome of the state of functioning of the vestibular system . if the vestibular system is negatively affected (“ one gets dizzy ”), standing balance deteriorates and the movement of the center of mass increases . in one embodiment of the present invention , the cnps is designed to target the vestibular system and hence standing balance is the appropriate outcome measure ( thomas et al ., 2001 a , b , c ). in a further embodiment of the present invention , the target of the cups is another system , such as the visual system and an outcome associated with vision is thus measured ( prato et al ., 2001 ). once a patient is set up within the system and a desired physiological function is selected for monitoring , the patient is then exposed to a desired cnps . an example of the one used to target the vestibular system is shown in fig9 . it is not necessary and in fact it is preferred that a volume coil not touch the patient as magnetic fields can penetrate tissue without direct contact with the volume coil . it is also preferred that the magnetic field exposure be monitored to ensure that the prescribed pulsed magnetic field ( cnps ) is actually produced by the volume coil ( thomas et al , 2001 a ). in the example of the vestibular system , the exposure protocol has the subject standing on the forceplate in the centre of the exposure system such that the uniform magnetic field of the volume coil is centred at head level . it is preferred that subjects stand with their feet slightly apart ( approximately 15 cm ) in the centre of the 3d forceplate with all forceplate values continually digitally recorded at 10 samples per second throughout the randomly assigned four 2 - minute exposures ( see fig9 ). using a standardised dialogue , subjects are asked to stand looking straight ahead with their eyes open and then be asked to slowly close their eyes , if required . each of the trials ( 2 minute trial , eyes open / closed , sham / pemf exposure ) ends with a short rest period ( approximate 30 s ). at the end of each rest period ( required for the operator to reset the data logger under computer control in a separate room and for the subject to relieve muscle tension ) , the next randomly assigned trial is initiated using the standardised dialogue . there should be no or minimal pemf / sham - related cues in the apparatus ( thomas et al , 2000 a ) thus ensuring the subject is blind to the exposure condition . in a further aspect of the present invention , objective or subjective measures may be made after the end of exposure to the cnps and compared to a baseline measurement made prior to exposure . in table 2 , it is demonstrated that the sway perturbing cnps produces a different result when comparing rheumatoid arthritis ( ra ) patients to fibromyalgia ( fm ) patients for the subjective measure of “ how bad is your pain right now ?” and “ how bad is your stiffness right now ?”. in still a further embodiment of the present invention the type of disease may be diagnosed and the severity of the disease diagnosed by comparing differential physiological effects from two different cnps exposures . as seen in table 5 , in mice exposed to a postural sway altering cnps results in different effects on different behaviours as compared to mice exposed to an analgesia - inducing cnps as seen in table 4 ( choleris et al ., 2001 ). as seen in fig1 , differential physiological effects occur in normal human subjects when exposed to different cnps and that for the same cnps , human patients with different diseases respond differently ( thomas et al ., 2001c ). in yet a further embodiment of the present invention , the type of disease and severity of the disease may be diagnosed by comparing differential physiological effects from the same cnps but under two different environmental conditions such as different light conditions . as seen in fig7 a , 7b , 8 a , 8 b , 10 and in table 3 , there are different responses under different light conditions to the same cnp ( prato et al ., 2001 ). as seen in fig4 and 6 there are different responses to the same cnp in patients with different underlying diseases ( thomas et al ., 2001c ). hence , diagnostic specificity and / or sensitivity should increase . in yet a further embodiment of the invention , the type of and severity of the disease maybe diagnosed by comparing differential physiological effects from the same or different cnps while being imaged with devices such as but not limited to functional magnetic resonance imaging ( fmri ) , position emission tomography ( pet or spect ) , magnetoencephalography ( meg ) , electromyography ( emg ) or electroencephalography ebg ). it is understood by those skilled in the art that other similar set ups are possible and within the scope of the invention . it is only important that the cnps exposure be relatively short and that the outcome measure is made during or after the exposure and the measures are compared . if the outcome device itself is perturbed by the cnps , then synchronisation of the measurements with the exposure is needed . for example , eeg and emg measurements would use devices that would pick up signal from this cnps . however , as the cnps design has short latency and longer refractory periods , where the magnetic fields are zero , measurements could be made during these periods . outcome measures are then analysed in a manner relevant to the cnps targeted tissue . in the example of the vestibular system , the measurements of the forceplate can be represented as a number of relevant parameters such as : total path , total area , total line and the total line can be broken down into the individual horizontal directions table 1 and 3 . fig4 shows typical measures of line ( in metres ) for three groups of human subjects : normals , patients with rheumatoid arthritis ( ra ) and patients with fibromyalgia ( fm ). fig5 shows how the outcome measures must be analysed such that the one sensitive to cnps exposure is properly quantified . here , the ‘ romberg quotient ’ shows that the vestibular system is perturbed by the pemw but not the sham exposure . the data is then appropriately analysed to separate patients into different disease categories dependent on how they responded to magnetic field exposure . examination of fig5 and fig6 indicate that ra and fm differ in their response to cnps and that each differ from the response of controls . subjects under all embodiments are kept unaware of whether they are being exposed or sham exposed as placebo effects can be large in human subjects . furthermore , exposure to other physical stimuli should be consistent for both sham and exposure . particularly important is the exposure to light intensity . fig7 a / b , 8 a / b and 10 show the results from human subjects exposed to different light intensities . in the 9 normal subjects ( mean age 26 . 4 ( sd 2 . 6 ); 6 male , 3 female ) exposed to a light intensity of 0 . 12 w / m 2 , statistical analysis of the data ( analysis of variance ) indicated that there was a significant increase in standing movement during pemp during eyes closed but not during eyes open . in a second experiment , 26 normal subjects ( mean age 26 . 9 ( sd 7 . 8 ) ; 13 male , 13 female ) were exposed in an identical protocol except horizontal light levels were increased to 0 . 51 w / m 2 ( 350 lux ). for this second group , standing balance was improved during pemf exposure while subject &# 39 ; s eyes were closed , a finding contrary to that found at the lower light intensity . it is clear from these results that the outcome measure from exposure to magnetic fields is affected by light intensity during that exposure , a result consistent with the literature on the effects of extremely low frequency magnetic fields on animal behaviour ( prato et al , 2000 ). this suggests that the preferred application of the method of the present invention may include control of light intensities during cnps exposure . further , that during single or multiple cnps exposure monitoring differential light intensities may improve the sensitivity and specificity of disease differentiation . the present invention has numerous applications in various industries where the determination and severity of true pain and general disability be identified . the examples are described for the purposes of illustration and are not intended to limit the scope of the invention . methods involved in magnetic field generation referred to but not explicitly described in this disclosure and examples are reported in the scientific literature and are well known to those skilled in the art . diagnostic discrimination of rheumatoid arthritis ( ra ) patients from fibromyalgia ( fm ) patients and both from healthy controls based on differential effects of pulsed magnetic fields ( cups ; 200 μt ) on normal standing . specific time varying pulsed magnetic fields ( cnps ) have been shown to alter subjectively assessed animal and human behaviours , including pain perception . the differential response to specific pulsed magnetic fields was used on standing balance and other behavioural measures to separate normal control patients from patients with different diseases or pathologies . patients were recruited , 15 ra ( mean ± sd 58 ± 12 . 4 ; 5 male , 10 female ) and 15 ra ( mean ± sd 45 ± 10 . 2 ; 15 female ) from a university hospital outpatient rheumatology clinic . all patients met the most recent american college of rheumatology ( acr ) disease classification criteria also recruited were 15 healthy controls ( mean ± sd 31 ± 7 . 4 ; 7 male , 8 female ) from among university students and personnel . each subject was placed within 3 square helmholtz coils ( 2 m × 1 . 75 m × 1 . 5 m ) ( thomas et al , 2000a ) , with each coil arranged orthogonal to the other two with the uniform magnetic field volume centred at head level for standing volunteers . fig1 fig2 ). subjects blind to study intent and exposure conditions stood with feet approximately 10 cm apart on the centre of the 3d forceplate . all forceplate and cnps ( 3d fluxgate magnetometer ) values were continually digitally recorded at 20 samples per second . each subject received four 2 - minute exposure conditions ( eyes open / closed , sham / cnps ) in a random order . standing balance was measured during each of the four exposures . a “ romberg quotient ” ( rq ) was calculated for sham and cnps exposures as the cumulative area of movement during normal standing balance with the “ eyes closed ” condition divided by the “ eyes open ” condition . data was analysed using anova and post hoc testing . [ 0107 ] fig3 shows a typical result in one patient with the pattern changing when the subject closes their eyes and when they are exposed to the cnps . fig4 and fig6 provide the raw data , the rq and results for 3 parameter reductions of the raw data . with eyes open and during sham exposure , fm patients and controls appeared to have similar standing balance while ra patients had worse standing balance ( fig4 ). with eyes closed , standing balance worsened for all three groups but more so for ra and fm patients than for controls ( fig4 ). the rq was highest among fm patients ( fig5 fig6 ). mixed design analysis of variance on the centre of pressure ( cop ) measurements show a significant interaction of eyes open / closed and sham / cnps conditions [ f = 8 . 78 ( 1 , 42 ), p & lt ; 0 . 006 ). rq of cop measurements improved significantly with cnps exposure [ f = 9 . 5 ( 1 , 42 ), p & lt ; 0 . 005 ] and cop path length showed an interaction approaching significance with clinical diagnosis [ f = 3 . 2 ( 1 , 28 ), p & lt ; 0 . 09 ]. from these sets of experiments it was evident that ra and fm patients and healthy controls differed with respect to standing balance and the effect of the cnps . the separation of ra patients from fm patients is of significant value as these patients are often given the wrong classification , ie . fm patients diagnosed incorrectly as ra patients and vice versa , especially in the initial manifestation of the disease . the ability to separate both these patients from normal controls especially fm from normal controls is extremely important in the scenario of workmen &# 39 ; s compensation benefits . among the medical community and among health insurers there is concern that individuals without true pain , fatigue or disability can feign pain , fatigue and / or disability and hence , be inappropriately classified as fm patients and receive compensation . it is also possible that true fm patients may not receive compensation as they cannot be objectively categorized . as the method of the present invention is entirely objective , it provides for the first time a measure which can be used to determine compensation rights . assessment of pain and analgesia in subjects exposed to a magnetic field ratios of electrical current ( ma time point / ma baseline ) were applied to the web of the left thumb required to produce a subjective “ moderate ” pain rating in male and female university students ( n = 11 ) while exposed to either a sham or pulsed magnetic field ( fig1 ). a ratio greater than 1 may be interpreted as an indication of analgesia ( or hypoalgesia ), and less than 1 , hyperalgesia . individual subjects were randomly assigned to either an analgesia - inducing magnetic field ( mn ) exposure ( n = 6 ) or postural sway altering mf group ( n = 6 ). sham and mf exposure trials were held at least one week apart and both experimenter and subjects were kept blind to the exposure conditions until the completion of the study ( double - blinded ). electric current recordings at each time point ( 15 - 60 min ) were divided by the baseline reading taken at time point 0 ( not shown ). time point 15 was a second control time point , with exposures ( sham or mw ) starting at time point 25 . the results show a significant interaction between me type ( analgesia vs . postural sway ) and exposure condition ( sham vs . mf exposed ) [ f1 , 9 = 8 . 9 , p & lt ; 0 . 032 , eta 2 = 0 . 64 ]. error bars represent the s . e . m . the above disclosure generally describes the present invention . a more complete understanding can be obtained by reference to the above specific examples . these examples are described solely for purposes of illustration and are not intended to limit the scope of the invention . changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient . although specific terms have been employed herein , such terms are intended in a descriptive sense and not for purposes of limitation . 1 . barker a . t ., freeston i . l ., jalinous r ., jarratt j . a . magnetic stimulation of the human brain and peripheral nervous system : an introduction and the results of initial clinical evaluation . neurosurgery 1987 , 20 , 100 - 109 . 2 . prato f . s ., kavaliers m . and thomas a . w . extremely low frequency magnetic fields can either increase or decrease analgesia in the land snail depending on field and light conditions . bioelectromagnetics 2000 ; 21 : 1 - 15 . 3 . choleris e ., thomas a . w . davaliers m ., prato f . s . a detailed ethological analysis of the mouse open field test : effects of chlorodiazepoxide diazepam and extremely low frequency pulsed magnetic field . neuroscience and behavioural reviews 2001 . 4 . thomas a . w ., drost d . j ., prato f . s . 2001a . a magnetic field exposure and behavioural monitoring system . bioeletromagnetics in press . 5 . thomas a . w . drost d . j ., prato f . s . 2001b . human subjects exposed to a specific pulsed magnetic field : effects on normal standing balance . neurosciences letters . 297 : 121 - 124 . 6 . thomas a . w . white k . p . drost d . j . cook c . m ., prato f . s . 2001c . a comparison of rheumatoid arthritis ( ra ) and fibromyalgia ( fm ) patients and healthy controls exposed to a pulsed magnetic field : effects on normal standing balance . neuroscience letters . accepted . 7 . prato f . s ., thomas a . w ., cook c . m . 2001 . human standing balance is affected by exposure to pulsed elf magnetic fields : light intensity dependent effects . nevroreport ( in press ). all publications , patents , and patent applications are incorporated by reference herein , as though individually incorporated by reference . [ 0120 ] table 2 pre - experiment , post - experiment , mean ( std dev ) mean ( std dev ) ra fm ra fm binary question ( no = 0 , yes = 1 ) do you have pain in your shoulders , arms or hands ? 0 . 80 ( 0 . 41 ) 0 . 86 ( 0 . 36 ) 0 . 60 ( 0 . 51 ) 0 . 86 ( 0 . 36 ) do you have pain in your hips , legs or feet ? 0 . 80 ( 0 . 41 ) 1 . 00 ( 0 . 00 ) 0 . 67 ( 0 . 49 ) 0 . 86 ( 0 . 36 ) do you have pain in your neck ? 0 . 47 ( 0 . 52 ) 0 . 86 ( 0 . 36 ){ circumflex over ( )} 0 . 33 ( 0 . 49 ) 0 . 79 ( 0 . 43 ){ circumflex over ( )} do you pain in your back ? 0 . 33 ( 0 . 49 ) 0 . 93 ( 0 . 27 ){ circumflex over ( )} 0 . 33 ( 0 . 49 ) 0 . 86 ( 0 . 36 ){ circumflex over ( )} do you have pain elsewhere ? 0 . 40 ( 0 . 51 ) 0 . 57 ( 0 . 51 ) 0 . 40 ( 0 . 51 ) 0 . 57 ( 0 . 51 ) analog pain scale ( 10 cm line ) 0 = none , 10 = very . how bad is your pain right now ? 3 . 34 ( 2 . 09 )↑ 4 . 96 ( 1 . 94 ){ circumflex over ( )}↑ 2 . 87 ( 2 . 09 ) 4 . 55 ( 2 . 50 ) how bad is your stiffness right now ? 3 . 13 ( 2 . 77 ) 4 . 36 ( 2 . 54 ) 2 . 50 ( 1 . 44 ) 4 . 28 ( 2 . 82 ){ circumflex over ( )} how tired or fatigued are you right now ? 4 . 26 ( 2 . 91 )↑ 5 . 32 ( 2 . 75 )↑ 2 . 99 ( 2 . 03 ) 4 . 56 ( 2 . 68 ) how weak do you feel right now ? 2 . 67 ( 1 . 90 ) 3 . 79 ( 2 . 40 ) 2 . 78 ( 2 . 50 ) 3 . 09 ( 2 . 67 ) how tense , nervous or anxious do you feel right now ? 1 . 80 ( 2 . 06 )↑ 2 . 64 ( 2 . 16 )↑ 1 . 63 ( 1 . 63 ) 1 . 77 ( 1 . 51 ) how dizzy do you feel right now ? 2 . 14 ( 2 . 50 ) 1 . 88 ( 1 . 93 ) 1 . 94 ( 1 . 76 ) 1 . 66 ( 1 . 62 ) [ 0121 ] table 3 table of results ( mean ± 1 s . e . m .) rq measure = eyesclosed measure eyesopen measure light intensity : 0 . 12 w / m 2 0 . 51 w / m 2 exposure : sham pemf sham pemf measure ( romberg quotient , rq ) line : 1 . 29 ± 0 . 14 1 . 78 ± 0 . 24 * 1 . 26 ± 0 . 08 1 . 14 ± 0 . 05 * path : 1 . 64 ± 0 . 14 1 . 88 ± 0 . 24 1 . 66 ± 0 . 10 1 . 69 ± 0 . 13 * significantly different between light intensities the interaction of light intensity and exposure is significant ( line : f 1 , 33 = 11 . 8 , p & lt ; 0 . 002 ). direction sensitivity ( mean axis shift difference ( m ), pemf - sham ) light intensity : 0 . 12 w / m 2 0 . 51 w / m 2 x axis : eo 4 . 805e − 04 ± 1 . 69e − 03 9 . 517e − 04 ± 6 . 45e − 03 ec 2 . 154e − 05 ± 3 . 06e − 03 1 . 915e − 03 ± 7 . 22e − 04 * y axis : eo 5 . 670e − 04 ± 1 . 25e − 03 1 . 242e − 03 ± 6 . 68e − 04 ec 2 . 532e − 04 ± 1 . 60e − 03 1 . 903e − 04 ± 8 . 40e − 04 * significantly different between exposure condition only . the interaction of light intensity and exposure is not significant ( p & gt ; 0 . 65 ). [ 0122 ] table 4 fig1 — summary of the effects of the first magnetic field exposure on open field behavior time course ( anova 0 × 1 ) overall sham - 1 mean comparisons mag - 1 mean comparisons anova 1 × 1 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 treat - tim × vs vs vs vs vs vs vs vs vs vs behavior time ment tre time 5 - 10 10 - 15 15 - 20 20 - 25 25 - 30 time 5 - 10 10 - 15 15 - 20 20 - 25 25 - 30 location corner + du h ns ns h ns s s h h h h h h h h wall fre h h ns h ns ns h h h h ns s s h s corner du ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns fre h h ns h ns ns s h h h ns ns s h h wall du h t ns s ns s t h s t ns s s h s fre h h ns h ns s h h h s ns t ns h s outer du h ns ns s ns t s s s s h s h h h ring fre ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns inner du h ns ns s ns s s h h h h h h h h ring fre h ns ns s ns h s s s h h h h h h central du h ns ns h h h s h h h s h h h h square fre s ns ns ns ns s ns s t ns s s ns ns ns loco - du h h ns h ns ns s h h h ns h s h h motion total fre t ns ns ns ns s ns ns ns ns s ns ns ns ns explore du h ns ns s ns ns ns s s h ns h s h h total fre h s ns ns ns ns ns ns ns h ns ns ns s s corner du h s ns h ns t h h h h h h h h h fre h h ns h s h h h h h h h h h h wall du h ns ns h ns ns t h s h ns h s h h fre h s ns h ns ns ns h h h ns h s h h outer du h ns ns s ns s s s s t s t h s s ring fre h ns ns t ns s t s t h h h h t s inner du h ns ns s ns s s h h h h h h h h ring fre h ns ns h t h s h h h h h h h h central du h ns ns h h h s h h s t h s h h square fre h ns ns h h h s h h s t h h h h walk du ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns total fre ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns corner du ns ns ns ns ns ns ns ns ns ns t ns ns t ns fre ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns wall du ns ns ns ns ns ns ns s ns ns ns ns ns ns ns fre s ns ns ns ns ns ns s s ns ns ns ns ns s outer du ns ns ns ns ns ns ns ns ns ns ns t t h s ring fre s ns ns ns ns ns ns ns ns s ns t s h s inner du ns ns ns ns ns ns ns ns ns t ns ns s s s ring fre s ns ns ns ns ns ns ns ns s ns ns s h s central du s ns ns ns ns ns ns t ns h ns ns ns h s square fre h ns ns ns ns ns ns ns ns h ns ns ns h h spin turn du h ns h s ns ns t ns ns h h h h h h total fre h ns ns t ns ns t ns s h s h h h h corner du ns ns ns ns ns ns ns ns ns ns t ns ns s fre ns ns ns ns ns ns ns ns ns ns ns s t ns s wall du s ns ns ns ns ns s ns ns s ns t ns h h fre h ns ns ns ns ns s ns ns h ns ns ns s h groom du h h ns s s h h h h t h h h h total fre h ns ns h s ns h h h h s h h h h corner du h ns ns s h s h s h s t h s ns t fre h ns ns h s s s s h s s s s s h wall du h ns ns h ns ns s s h t ns ns ns s ns fre h ns ns h ns ns s s h t ns ns ns s s sit du s ns ns s ns ns ns ns h ns ns ns s ns ns total fre t ns ns ns ns ns ns ns t ns ns ns s ns ns corner du ns ns ns s ns ns ns ns h ns ns ns ns ns ns fre ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns wall du ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns fre ns s ns ns ns ns t ns ns ns ns ns ns ns ns outer du ns ns ns ns ns ns ns ns t ns ns ns ns ns ns ring fre ns ns ns ns / / / ns ns ns / / ns ns / stretch fre h ns ns h h h h h h h h h h h h attend total corner fre h ns ns h h h h h h h h h h h h wall fre h ns ns h h h h h h h h h h h h outer fre h ns ns h h h h h h h h h h h h ring inner fre h ns ns t s ns ns t s h ns ns h h h ring central fre h ns ns ns t ns ns ns s h ns ns h h h squa return fre h ns t h h h h h h h h h h h h total corner fre h ns ns h t h h h h s h h h h h wall fre h ns t h h h h h h h h h h h h rear fre h ns ns h s h h h h h h h h h h total corner fre s ns ns ns t s s ns ns ns s ns ns ns ns wall fre h ns ns h s h h h h h h h h h h outer fre h ns ns h ns h h h h h h h h h h ring inner fre h ns ns h ns h h h h h h h h h h ring central fre h ns ns h ns s ns h h ns ns s ns s s squa direct effect of treatment manova 0 - 5 - 10 - 15 - 20 - 25 - behavior 5 10 15 20 25 30 location corner + du ns ns ns ns ns ns wall fre h h h s t s corner du ns ns ns ns ns ns fre t ns h s ns t wall du ns ns ns ns ns ns fre h h s s ns ns outer du ns ns ns ns ns ns ring fre t ns t ns ns ns inner du ns ns ns ns ns ns ring fre s ns ns ns ns ns central du ns ns ns ns ns ns square fre ns ns ns ns ns ns loco - du ns t h ns s ns motion total fre ns ns s ns ns ns explore du ns ns t ns ns ns total fre ns ns s ns ns ns corner du ns s s s ns ns fre ns s h s ns s wall du ns ns ns ns ns ns fre ns ns s s ns ns outer du ns t ns ns ns ns ring fre ns ns ns ns ns ns inner du ns t ns ns ns ns ring fre ns ns ns ns ns ns central du ns ns ns ns ns ns square fre ns ns ns ns ns ns walk du ns ns ns ns ns ns total fre ns ns ns ns ns ns corner du ns ns ns ns ns ns fre ns ns ns ns ns ns wall du ns ns ns ns ns ns fre ns ns ns ns ns ns outer du ns ns ns ns ns ns ring fre ns ns ns ns ns ns inner du ns ns ns ns ns ns ring fre ns ns ns ns ns ns central du ns ns ns ns ns ns square fre ns ns ns ns ns ns spin turn du ns h s ns ns ns total fre ns ns ns ns ns ns corner du ns ns ns ns ns ns fre ns ns t ns ns ns wall du ns ns t ns ns ns fre ns ns ns t ns ns groom du ns ns s ns s ns total fre ns ns t ns ns ns corner du ns ns ns ns ns ns fre ns ns ns ns ns ns wall du ns ns t ns ns ns fre ns ns ns ns ns ns sit du ns ns ns ns ns ns total fre ns ns ns ns ns ns corner du ns ns ns ns ns ns fre ns ns ns t ns ns wall du ns ns ns ns ns ns fre ns ns ns ns ns ns outer du / / / ns ns ns ring fre / / / ns ns ns stretch fre ns ns ns ns ns ns attend total corner fre ns ns ns ns ns ns wall fre ns t ns ns ns ns outer fre ns ns ns ns ns ns ring inner fre ns ns ns ns t ns ring central fre ns s ns ns ns ns squa return t ns ns ns ns ns total corner fre ns t ns / / / wall fre t ns ns ns ns ns rear fre ns ns ns ns ns ns total corner fre ns ns ns t ns ns wall fre ns ns ns ns ns ns outer fre ns ns ns ns ns ns ring inner fre ns ns ns ns ns ns ring central fre ns ns ns ns ns ns squa [ 0123 ] table 5 fig1 — summary of the effects of the second magnetic field exposure on open field behavior time course ( anova 0 × 1 ) overall sham - 2 mean comparisons mag - 2 mean comparisons anova 1 × 1 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 0 - 5 treat - tim × vs vs vs vs vs vs vs vs vs vs behavior time ment tre time 5 - 10 10 - 15 15 - 20 20 - 25 25 - 30 time 5 - 10 10 - 15 15 - 20 20 - 25 25 - 30 location corner + du h ns ns h t h h h t h h h h h h wall fre s ns ns ns ns t s ns ns t ns ns ns ns ns corner du ns ns ns ns ns ns ns ns ns ns ns ns ns s ns fre ns ns ns ns ns ns ns ns ns ns ns wall du h ns ns s ns ns ns h s s ns s ns ns h fre ns ns ns ns ns ns ns ns ns t ns ns ns ns t outer du h ns ns h h h h h h h h h h h h ring fre ns ns ns ns ns ns ns ns ns ns ns ns ns ns s inner du h ns ns t ns s h s ns h h h h h h ring fre h ns ns h h h h h h h h h h h h central du h ns ns s h s h ns ns h h h h h s square fre s ns ns ns ns ns ns ns ns h h s ns ns ns loco - du h t ns h ns ns t h h h s h h h h motion total fre h t t s h h h s h h h h h h s explore du h ns ns h ns ns s h h h ns ns s t h total fre h ns t h ns ns ns t t h h s ns s ns corner du h t ns h s h h h h h s h h h h fre h ns ns h ns s h h h h ns s h h h wall du h ns ns h ns ns s h h h ns s h h h fre h ns s h ns ns ns h h h s ns ns ns h outer du h ns ns h s h h h s h h h h h h ring fre h ns ns h h h h s t h h h h h h inner du h ns ns ns ns s s ns ns h h h h h s ring fre h ns ns h h h h s t h h h h h h central du h ns ns s h s s ns ns h h h h h s square fre h ns ns t s s s t ns h s h h h s walk du ns ns ns ns ns ns ns ns ns ns t ns ns s ns total fre h ns ns ns ns s t t s s s s ns h t corner du h ns ns s ns ns h s s s ns s h s h fre h ns ns s ns ns t ns ns s ns ns t ns ns wall du ns ns ns ns ns ns ns ns ns ns t ns ns ns ns fre ns ns ns ns ns ns ns ns ns ns s ns ns ns ns outer du h ns ns h ns h h h h h ns s s h h ring fre h ns ns h t h h h h h ns h h h h inner du h ns ns h ns s s h h h ns ns s h s ring fre h ns ns h ns s s h h h ns s h h h central du s ns ns t ns ns h s s ns ns ns ns ns s square fre h ns ns s ns ns h s s ns ns ns ns ns s spin turn du h ns h h ns h s h h h h ns s ns s total fre corner du ns h ns ns ns s ns s s ns ns ns t ns ns fre s s ns ns ns s ns s s t ns t h ns ns wall du h ns ns ns ns s ns ns s s ns s h ns t fre h ns ns s ns h ns s h h ns h h h s groom du h h ns h s h h h h h s h h h h total fre h s ns h s h h h h h h h h h h corner du h ns ns ns ns s s s s h ns h h ns h fre h ns ns ns ns s s s s h s h h s h wall du h s ns s ns ns t s h ns ns ns s ns s fre h s ns h ns s s s h ns ns ns s t ns sit du ns ns ns ns ns ns ns ns ns ns ns ns ns t t total fre s ns ns ns ns ns s ns ns t ns ns s s s corner du ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns fre ns ns ns ns ns ns ns ns t ns ns ns ns ns ns wall du s s ns ns ns ns ns ns ns ns ns ns t ns ns fre ns ns ns ns ns ns ns ns ns ns ns ns s ns t outer du ns ns ns ns ns ns t ns ns ns ns ns ns ns ns ring fre ns ns ns ns ns ns s ns ns ns ns ns ns ns ns stretch fre h ns ns h h h h h h h h h h h h attend total corner fre h ns ns h h h h h h h h h h h h wall fre h ns ns h h h h h h h h h h h h outer fre h ns ns h h h h h h h h h h h ring inner fre h ns ns t s ns t t h h ns ns h h h ring central fre h ns ns ns t ns ns ns s h ns ns h h h squa return fre h ns t h h h h h h h h h h h h total corner fre h ns t h h h h h h s ns h h h h wall fre h ns ns h h h h h h h h h h h h rear fre h ns ns h h h h h h h h h h h h total corner fre h ns ns h h h h h h h h h h h h wall fre h ns ns h h h h h h h h h h h h outer fre h ns ns h h h h h h h h h h h h ring inner fre h ns ns h h h h h h h t h h h h ring central fre h t ns s ns h s s s h ns ns h h t squa direct effect of treatment manova 0 - 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