Behavioral Spectoscopywith the Force-Plate Actometer by zcx31478


									Behavioral “Spectoscopy” with the
Force-Plate Actometer

Stephen C. Fowler, Ph.D.                                             Monitoring the behavior of animals is an important tool for screening
Departments of
                                                                     potential new drugs for both effectiveness and safety. This article describes
Human Development and                                                a unique approach capable of detecting subtle effects that are in many cases
Pharmacology and
                                                                     not measurable with standard methodology. Pharmaceutical and biotech-
                                                                     nology companies must correlate behavior information with chemical data
University of Kansas
Lawrence, KS 66045
                                                                     (pharmacology, clinical chemistry and drug metabolism), physiological data
                                                                     (blood pressure, electrocardiograms, EEGs, etc.) and pathology data to
                                                                     arrive at a final conclusion.

                                                                     Supported in part by MH43429 and DA12508.

                           Basic biobehavioral research has re-           Though it often goes without be-      gene and protein function in health
                           lied heavily on behavioral measure-       ing said, most scientist would agree       and disease, will become ever more
                           ments in animals as a key part of the     that, “Instruments shape research,         important. The force-plate actome-
                           scientific discovery process. Alzhe-      determine what discoveries are             ter affords the means to extract large
                           imer’s disease, Parkinson’s disease,      made, and perhaps, even select the         quantities of functional information
                           drug abuse, psychiatric disorders         types of individuals likely to succeed     from a single recording session (e.g.,
                           (schizophrenia, depression, etc.),        as scientists.” (1) Inherent in the sci-   distance traveled, number and dura-
                           analysis of brain circuits, and mo-       entific instrument is the capacity to      tion of wall rears, presence and fre-
                           lecular genetics (e.g., knockout          render reliable quantitative measure-      quency of tremor, gait disturbance,
                           mice), have all relied on rodent mod-     ments. In the behavioral field, this       rotations, rhythmicity of stereoty-
                           eling efforts that have measured lo-      has always been a challenge, yet few       pies, and more). As such, this ap-
                           co mo tor      activity,       tremor,    have undertaken the task of develop-       proach to behavioral measurement,
                           stereotypies, and rotational behav-       ing new instruments with a relatively      when combined with the necessary
                           ior, to name a few of the behaviors       wide range of applications. The need       computer algorithms, will be able to
                           that can be quantitated with the          for improved behavioral measure-           provide for relatively high through-
                           force-plate actometer. A force-plate      ments is acutely illustrated by a re-      put, multi-dimensional screening for
                           actometer is an instrument that uses      cent mouse behavioral genetics             gene manipulations in mice or rats.
                           a horizontal sheet of stiff lightweight   study (2) that showed how difficult             Overall, the significance of this
                           metal supported by four force             it is to replicate behavioral measure-     instrument is that it will provide for
                           transducers to measure the attributes     ments across laboratories. The             better quantification of behavior
                           of the behavior of an animal that         greater temporal and spatial resolu-       than has heretofore been possible,
                           moves around on the horizontal            tion of the force-plate actometer          and it will achieve this with a single
                           sheet or plate. It measures the dis-      compared to existing instruments           instrument. Availability of this in-
                           tance traveled, as do conventional        should make it possible to achieve         strument to life scientists around the
                           photobeam actometers, but the             quantitative reliability across labora-    world will accelerate preclinical
                           force-plate approach allows for a         tories studying rodent behavior as an      biomedical discovery related to a
                           much broader and higher precision         end point.                                 broad range of central nervous sys-
                           look at behavior than the photobeam            With the advent of the decipher-      tem disorders.
                           or video methods. Thousands of pa-        ing of the mouse genome and the                 Despite widespread use of pho-
                           pers have been published involving        dawning of the proteomics era, be-         tobeam-based systems to measure
                           the measurement of these behaviors        havioral measurement as a window           the effects of drugs, lesions, or gene
                           with disparate types of instruments.      into brain function and, therefore,        manipulations in rodents, these de-

17                                                                                                                        Current Separations 20:1 (2002)
                                vices have limited spatial and tem-      tious positioning of the rat with re-    of whole-organism behavioral at-
                                poral resolution for describing be-      spect to a particular photobeam.         tributes relevant to basic neurosci-
                                haviors of interest. (A substantial      Therefore, this latter method carries    ence research. A force-sensing plate
                                amount of this paper is quoted or        with it a considerable amount of un-     is used to quantify an animal’s move-
                                paraphrased from ref. 3.) For exam-      specified error that can only be aver-   ments that are confined to a horizon-
                                ple, even the “high resolution” sys-     aged out by using larger numbers of      tal sensing area by an enclosure
                                tems have beam spacings of about         subjects. Consequently, direct obser-    suspended a short distance (2 mm)
                                2.5 cm. When the species of interest     vational methods for quantifying         above the upper surface of the force
                                is the mouse, this spatial resolution    amphetamine-induced stereotypies         plate. The enclosure may be either
                                is only one-half a body length, and      continue to be in widespread use         square or cylindrical, depending on
                                this quantizing error may make it        (5,6). Of course, such observational     the aims of the research. In order for
                                difficult to detect patterns of behav-   methods are labor intensive and do       the positional information of the ani-
                                ior more complex than movement           not lend themselves to quantitation      mal’s movements to be referred to
                                from place to place. Another long-       based on frame-by-frame scoring of       the same coordinate system across
                                standing experiment for which the        video recordings by human ob-            different recording instruments, the
                                photobeam apparatus is not well          servers. The force-plate actometer       position of the enclosure must be
                                suited is measuring amphetamine-         provides for computer scoring of         precisely (+/- 0.5 mm) specified in
                                induced stereotypies (4), because        amphetamine-induced stereotypies.        relation to the force plate. This is
                                stereotypies occur when the rat is not   The instrument has both spatial and      accomplished by guide holes that ac-
                                locomoting. In the photobeam appa-       temporal resolution that far exceeds     cept the “feet” that support the en-
                                ratus, counting consecutive breaks       the photobeam methods, and in ad-        closure (see F1, bolt near lower right
                                of the same beam has been claimed        dition to allowing for machine scor-     corner of photo). A description of the
                                to be a measure of stereotypy, but       ing of amphetamine-induced               components and their assembly into
                                this method depends on the propi-        stereotypies, the instrument can         a functioning instrument will be
                                                                         quantify whole-body tremor, rota-        aided by reviewing the physical prin-
F1                                                                       tional behavior, and locomotor activ-    ciples that serve as the essential con-
A prototype force-plate                                                  ity from a single session of data        cepts upon which the measurements
actometer with a CD-1
mouse on the
                                                                         recorded from either rats or mice.       are based.
force-sensing plate. The                                                 The type of behavioral measurement            F2 shows a diagram of the force-
housings of two of the four
force transducers are
                                                                         is determined by the kind of software    plate recording area as viewed from
visible as shiny cylinders                                               applied to the raw data.                 above. The four forces f1, f2, f3, and
underneath the front left
and front right corners of
                                                                             A force plate actometer is an en-    f4 correspond to the four corners of
the Plexiglas cage that                                                  semble of mechanical, electronic,        the force plate and are permanently
confines the mouse to the
recording area. From
                                                                         and computing elements that em-          defined by rigid physical coupling of
reference 3.                                                             body mathematical and physical           four force transducers to the force
                                                                         principles to produce measurement        plate material. The fixed locations of
                                                                                                                  the four forces are given by their
F2                                                                                                                coo rdin ate locations (X1,Y1),
Diagram of the coordinate
                                            f2                                             f1                     (X2,Y2), (X3,Y3), and (X4,Y4), re-
system defined by the four        X2=-140 mm                                                    X1= 140 mm
force transducers.                Y2=140 mm           Quadrant II           Quadrant I          Y1= 140 mm        spectively. In this description of
Symbology is explained in                                     x c=-70                                             principles, lower case symbols rep-
the text related to                                           y c=115                                             resent variables, and uppercase sym-
formulas (1) and (2). f1,
f2,f3, and f4 represent the                                                         =70
                                                                                   xb                             bo ls represent con stants. By
force measures read from                                                            =70
the four force transducers                                                                                        convention (in the disciplines of
that support the plate on                                =35
                                                        yd                                                        mathematics and physics), the four
which the animal walks.
X-Y pairs represent                                                                                               support transducers measuring the
coordinates, with capital                                                xa
                                                                          =0                                      four component forces are ordered in
letters representing                                                      =0
constants and lower case                                                                                          a counterclockwise fashion with f1
letters representing                                                                                              representing the force in Quadrant I
variables. The enclosure
that confines the animal to                                                                                       (the quadrant in Cartesian coordi-
the plate is designed so                                                                                          nates where x and y are positive).
the inside corners of
enclosure vertically align                                                                                        The position of a force applied to the
with coordinates                 X3=-140 mm           Quadrant III          Quadrant IV         X4=140 mm         force plate can be calculated by mak-
representing the four            Y3=-140 mm f
corners of the force plate                    3                                            f4   Y4=-140 mm        ing use of the four forces sensed at
(i.e., X1, Y1 is the location                                                                                     the fixed locations defined by the
of corner 1 and the
location of transducer 1).                                                                                        support points. If a force is applied
From reference 3.                                                                                                 to the horizontal force plate at a point                                                                                                                          18
     exactly equidistant between each of       tion of a mouse on the force plate is             C57BL/6 male mice from Char-
     the four support points (namely, at       defined by the center of force, and           les River Laboratories were main-
     xa=0,ya=0, the center of the coordi-      the position coordinates become the           tained under unrestricted feeding
     nate system), then the forces sensed      basis for calculating distance trav-          and watering conditions. The tre-
     at the four support points will sum to    eled, area covered, spatial pattern,          morogenic effects of one dose of
     the force in the center. If the applied   etc. A sample calculation of distance         10.0 mg/kg of harmaline hydrochlo-
     force is moved along a diagonal from      in Cartesian coordinates is as fol-           ride were studied when the mice
     xa=0,ya=0 toward (X1, Y1), the f1         lows: the distance between points c           were about 20 weeks old. An in-
     force at (X1,Y1) will rise and the f3     and d (see F2) is:                            traperitoneal injection of the drug
     force at (X3,Y3) at the opposite end                                                    was given about 5 s before the start
                                                                    2             2 1/2
     of this diagonal will fall in propor-     Distance = ((xc-xd) + (yc-yd) )               of a 30 min recording session in the
     tion to the distances involved.                                                         actometer. The recording scheme for
                                                                        2            2 1/2
          An example is shown as a point       Distance = ((-70-35) + (115-35) )             purposes of the Fourier analysis of
     in the center of Quadrant I in F2. A                                                    the force signals from the plate was
     100-gram weight placed at point b         so Distance = (6125)           or 78.3 mm.    45 consecutive force time series of
     (xb,yb) will result in force measure-                                                   40.96 s in length or 2048 samples at
     ments of 60g, 15g, 10g and 15g, for            The force measurements re-               50 samples/s. Each force datum was
     f1, f2, f3 and f4, respectively. The      corded across time (as opposed to             the sum of the forces from the four
     relation between the location of the      the position measurements) serve as           individual transducers that sup-
     center of applied force and the four      the basis for detecting the rhythmi-          ported the force plate. Exploratory
     forces at the support points is ex-       cities of the force variations exhib-         analyses showed that using the sum
     pressed by these two equations:           ited during walking, jumping,                 of the four forces did not distort the
                                               stereotypies, or tremor. The force            spectrum compared to an analysis
     x = (X1 f1 + X2 f2 + X3 f3 + X4 f4) /     measurements are for a vertical force         b ased o n the data from each
     (f1 + f2 + f3 + f4) (1)                   vector (Fz) b ecause the for ce               transducer performed separately.
                                               transducers sense vertical forces.            Each of the 45 force-time series was
     y = (Y1 f1 + Y2 f2 + Y3 f3 + Y4 f4) /     The power spectra referred to in the          subjected to an FFT (with Hanning
     (f1 + f2 + f3 + f4) (2).                  following examples are based on               data window). The resulting power
                                               analyses of Fz(t), the vertical force as      spectra were examined individually,
         Thus, the sum of f1, f2, f3 and f4    a function of time.                           and the harmaline recording session
     represents the applied force and each                                                   was compared to a prior saline re-
     of these four separate forces repre-      Measuring Tremor                              cording session by ensemble averag-
     sents the reactive forces supporting                                                    ing the 45 power spectra separately
     the force plate with the load force       Tremor is a prominent behavioral              for the drug and saline sessions.
     applied. Different symbols for the        end point reflective of CNS dysfunc-              F3 shows force-time recordings
     applied force and the reactive sup-       tion caused by disease (e.g., Parkin-         for three frames taken from the har-
     port forces are not used because          son’s disease) or by toxins (e.g.,            maline recording session. Frame 1
     physical principles demonstrate that      heavy metal intoxication). Despite            (40.96 s of recording, beginning 5 s
     these applied and reactive forces are     its importance in neuroscience re-            after dosing) shows the force vari-
     equal. Equations (1) and (2) provide      search, tremor measurement in ro-             ations during movements around the
     the basis for calculating the position    dents has often rested on the use of          force plate. In frame 10 (about 405 s
     of the center of force when the indi-     rating scales by human observers;             after the injection), the first expres-
     vidual reactive or support forces are     however, sophisticated direct-meas-           sion of tremor was detected.
     k nown (i.e., via the force               urement, instrumental methods have                It should also be noted that the
     transducers). When an animal is the       been developed for the specific pur-          force variations had subsided to a
     load on the force plate, both the ap-     pose of quantitating whole-body               relatively low level before the tremor
     plied force at any instant and the        tremor (7). The force-plate actome-           was first expressed. This inactivity
     position of the center of force at any    ter, without modification of its loco-        may be reflecting nervous system
     instant will vary with time as the        motor measurement capabilities, can           changes that precede tremor onset.
     animal moves. Provided the meas-          be used to quantitate whole-body              By Frame 20, the tremor was well
     urement of the four forces at the plate   tremor. Inasmuch as harmaline is              developed, but it was not continuous
     support points are taken rapidly          frequently used as a model of essen-          across the entire 40.96-s frame.
     enough and the plate and mass of the      tial tremor observed in the clinical          Power spectra for recording frames
     sensors are low in relation to the        setting (8), this drug was used to            1, 10 and 20 are shown in F4 (top).
     applied force, the position of the cen-   demonstrate drug-induced tremor in            Harmaline induced a concentration
     ter of force is independent of the        the C57BL/6 mouse.                            of power in the 12-18 Hz region, and
     actual applied force. Thus, the posi-                                                   the frequency of the dominant peak

19                                                                                                     Current Separations 20:1 (2002)
                             in the spectrum was at a lower fre-                  The force-plate approach to tremor         ment with the same dose) are promi-
                             quency in frame 20 compared to                       measurement was successfully con-          nent (6). Amphetamine-induced
                             frame 10. The reliability and mean-                  ducted in harmaline-treated rats           stereotypies in rats have been used as
                             ing of this latter frequency-shift phe-              (10).                                      an animal model of schizophrenia
                             no meno n        requires further                                                               (12) and have figured prominently in
                             investigation. Power spectra from                    Quantifying Focused                        theories of basal ganglia function
                             the entire saline and drug sessions                  Stereotypies in                            (2,13). Stereotypies in rodents have
                             for this mouse are shown in the bot-                 Amphetamine-Treated Rats                   been scored by human observers
                             tom axes of F4. The predominant                                                                 who use rating scales. Such methods
                             peak of the harmaline spectrum was                   Amphetamine and other drugs that           vary from laboratory to laboratory
                             centered at about 13 Hz, and the                     increase the brain action of the           and are dauntingly labor-intensive.
                             spectrum for the saline session con-                 neurotransmitter dopamine induce           Therefore, objective, instrument-
                             tained relatively greater power at the               in rats a state of behavioral activation   scored stereotypies would be a use-
                             lower frequencies (0-5 or 6 Hz) than                 that at low doses produces increases       ful methodology in this area of
                             the spectrum for the drug session.                   in locomotor activity and at higher        research. The force plate actometer
                                 The force-plate actometer suc-                   doses leads to highly repetitive,          was used to “machine score” these
                             cessfully quantitated tremor in the                  rhythmic behaviors such as nose            amphetamine-induced stereotypies
                             C57BL/6 mouse treated with the                       poking, sniffing, head-bobbing and         with unparalleled temporal and spa-
                             tremor-inducing agent harmaline.                     licking, but no locomotion. These          tial resolution.
                             The attributes of the tremor were                    high-dose phenomena are collec-                 Male Sprague-Dawley rats ob-
                             consistent with reports in the litera-               tively referred to as stereotypies         tained from Harlan Laboratories,
                             ture with respect to frequency (9),                  (11), and sensitization effects (in-       and weighing 250 g, were treated
                             but the intermittent expression of the               creasing tendency to engage in             with 2.5 mg/kg d-amphetamine sul-
                             tremor may be strain dependent (9).                  stereotypies upon repeated treat-          fate once a day according to the
                                                                                                                             schedule previously described (6),
                                C57BL/6 #2, Harm 10 mg/kg, Frame 1

                                                                                                                             which consisted of drug injections
Time series plots of force
variations (Fz) produced                                                                                                     on days 1, 2, 3, 4, 5, 6, 7, 9, and 21
by a male C57BL/6                                                                                                            over a 21 day period. One-hour ses-
mouse administered 10.0
mg/kg harmaline a few                                                                                                        sions were used. Sample data for one
seconds before the                                                                                                           rat are shown in F5. The one-hour
recording of frame 1
commenced. In frame 10                                                                                                       session was divided into 3-minute
the first indication of                                                                                                      time blocks and the power spectra of
harmaline tremor within
the 30 min. session                                                                                                          the force variations (Fz(t)) were cal-
appeared. By frame 20,                                                                                                       culated for each time period (column
tremor was pronounced,
but not continuous. From                                                                                                     A in F5).
                                C57BL/6 #2, Harm 10 mg/kg, Frame 10

reference 3.                                                                                                                      Column D of F5 shows that am-
                                                                                                                             phetamine produced a phase of loco-
                                                                                                                             motor stimulation early in the
                                                                                                                             session, but this tendency to move
                                                                                                                             around the chamber gave way to a
                                                                                                                             state of no locomotion in time bocks
                                                                                                                             7-20. The narrow-band peaks in the
                                                                                                                             power spectra near 10 Hz and the
                                                                                                                             peaks at 2.5 Hz were evident by time
                                                                                                                             block 5 (15 min.). To our knowledge
                                                                                                                             these kinds of data showing that am-
                                C57BL/6 #2, Harm 10 mg/kg, Frame 20

                                                                                                                             phetamine induces narrow-band
                                                                                                                             rhythmic behavior near 10 Hz are
                                                                                                                             first time observations. Ampheta-
                                                                                                                             mine-induced focused stereotypies
                                                                                                                             are characterized by a high degree of
                                                                                                                             rhythmicity, which at this high 10 Hz
                                                                                                                             repetition rate likely reflect underly-
                                                                                                                             ing neural events operating at the
                                                                                                                             same frequencies. In F5, column A,
                                                                      25 g
                                                                                                                             one can discern a gradual within-ses-
                                                                             1s                                              sion drift in the frequency of the                                                                                                                                    20
                               dominant peak in the spectrum from     spectral power in the 0-0.5 Hz low        the drug. Importantly, the data
                               about 10 Hz to about 11 Hz. This       frequency band, but when there was        shown in F5 indicate that in the first
                               frequency shift phenomenon has         no locomotion very little power was       18 minutes of the recording session
                               now been replicated in over a dozen    detected in this frequency band. At       focused stereotypies are intermixed
                               rats. The stereotypy score shown in    the same time, the power in the peak      with some locomotion (see, for ex-
                               Column C of F5 was calculated from     near 10 Hz increased as locomotion        ample, time blocks 4-6 and compare
                               the power spectra. It was observed     ceased. These observations led to the     columns A and D of F5).
                               that the periods of high locomotion    calculation of the focused stereotypy          It is interesting to note that the
                               (e.g., time blocks 1 and 2) were ac-   score plotted in column C of F5. This     distance measure (column B) was
                               companied by concentrations of         score is the logarithm of the ratio of    relatively constant throughout the
                                                                      the average power in the 8-13 Hz          session despite the switch from loco-
                                                                      band to the average power in the          motion to focused stereotypies. This
The upper panel shows                                                 0-0.5 Hz frequency band. This score       means that the distance moved by the
the power spectra of the
time series plotted in F3.                                            reflects well the combination of in-      center of force (resolved to less than
In the lower panel are                                                tense behavior (primarily head            1 mm) during locomotion was nearly
ensemble averaged
(across 45 frames of                                                  movements) and spatial confine-           the same as the distance for the fo-
2048 samples each or                                                  ment that are the hallmarks of the        cused stereotypies, in which dis-
40.96 s) power spectra
for the harmaline (10                                                 focused stereotypy “syndrome” (6).        tance was produced by relatively
mg/kg) session and for a                                              These head movements are often de-        high-frequency, small-amplitude
saline control session that
preceded the drug                                                     scribed as head bobbing, rapid lat-       movements of the rat’s head. Others
treatment.                                                            eral head movements or sniffing.          (14) have shown that a combination
                                                                      Moreover, unlike similar scoring          of force and distance measurements
                                                                      schemes based on human observers          taken from a force-plate can be used
                                                                      using time sampling, our approach to      to estimate energy expenditure of the
                                                                      quantifying stereotypies captures all     organism moving on the plate. The
                                                                      the data with a time resolution suffi-    implication here is that distance in
                                                                      cient to describe the onset kinetics of   F5 remained relatively constant
                                                                                                                across session time because the en-
F5                                        A                 B                   C             D                 ergy expenditure for focused stereo-
                                                                                                                typies was approximately the same
Power spectra of
variations in vertical force                                                                                    as for locomotion when the animal
(A), distance traveled by                                                                                       was affected by 2.5 mg/kg ampheta-
the center of force (B),
spectrally-based                                                                                                mine. The fact that the rat was not
stereotypy score (C), and                                                                                       locomoting around the chamber can
movement trajectory of
the center of force as                                                                                          be shown numerically (but not
viewed from above the                                                                                           shown graphically in F5) by calcu-
recording chamber (D) for
one rat that received 2.5                                                                                       lating the number of low mobility
mg/kg seconds before                                                                                            bouts observed during each 3 minute
being placed in the
force-plate actometer.                                                                                          period within the session. A low mo-
These data are for the 9th                                                                                      bility bout was defined as spatial
experience of the drug
treatment that occurred                                                                                         confinement to a 4 cm diameter cir-
on day 21 of the dosing                                                                                         cle for 10 s (a maximum of 18 such
regimen. Unpublished
observations.                                                                                                   bouts in a 3-minute period). Apply-
                                                                                                                ing this criterion to the spatial coor-
                                                                                                                dinate data indicated the number of
                                                                                                                low mobility bouts in the first 3 min-
                                                                                                                utes was 0, and it reached 18 bouts
                                                                                                                by the 8th time block and remained
                                                                                                                at 18 bouts through the end of the
                                                                                                                     We have learned from frame-by-
                                                                                                                frame video analysis and from spec-
                                                                                                                tral analysis of spatial coordinates
                                                                                                                (as opposed to the vertical force vari-
                                                                                                                ations) that the peaks at 2.5 Hz rep-
                                                                                                                resent lateral movements of the rat’s
                                                                                                                head during prolonged bouts of

21                                                                                                                        Current Separations 20:1 (2002)
                       “sniffing” and/or “head bobbing”        scribed empirical demonstrations.          References
                       characteristic of focused stereotypy    With the proper software it will be
                       (data not shown for the sake of brev-   possible to detect and quantify wall       1.      .H.
                                                                                                                P Abelson, Amer. Sci. 74 (1986)
                       ity). Other analyses not shown here     rears, gait disturbances, jumping,
                                                                                                          2.    J.C. Crabbe, D. Wahlsten and B.C.
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                                                                                                          6.    J.J. Canales and A.M. Graybiel, Nat.
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                       in the 2.5 to 5.0 mg/kg dose range.     low for the simultaneous evaluation
                                                                                                          9.    T.E. Milner, G. Cadoret, L. Lessard
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                                                                                                                Psychopharma. 11 (1967) 300-10.
                       ing to their frequency components is    the force-plate methods should make
                                                                                                          12.   G.D. Ellison and M.S. Eison,
                       analogous to the separation of mole-    it possible to quantitate assimilation           Psychol. Med. 13 (1983) 751-61.
                       cules in NMR spectroscopy, and this     and elimination drug kinetics              13.   A.M. Graybiel, J.J. Canales and C.
                       separation analogy informs the title    through the use of behavioral vari-              Capper-Loup, Trends in Neurosci.
                       of this article.                        ables.                                           23 (2000) s71-s77.
                           Potential uses of the force-plate                                              14.   M. Sun and J.O. Hill, J. Biomech 26
                                                                                                                (1993) 229-241.
                       actometer go beyond the above-de-                                                                                                                     22

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