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Modulation of the thalamocortical motor system by sensory information
BRAIN RESEARCH
35
MODULATION OF THE THALAMOCORTICAL MOTOR SYSTEM BY SENSORY INFORMATION
R N JOHNSON* ANDG R HANNA Department of Neurology, Umverstty of Vtrgmla School of Medicine, Charlotteswlle, Va 22901 (usa)
(Accepted September 3rd, 1971)
INTRODUCTION Numerous investigators have studied the influence of peripheral signals on both thalamlc structuresa,9,10,1a and single neurons within sensorimotor cortex1,2,4,14-1e The polysensory nature of cat sensorImotor cortex, particularly precruciate tissue, has been shown, responding to light, sound and somatic inputs 11 We have previously considered the dynamic aspects of the ventrolateral (VL) thalamic-sensorlmotor (MC) cortical system from the more general Input-output viewpoint7,s We have recently shown that the VL-MC system in the cat can be consldered to be approximately linear over a restricted range of responses and that the slope of the approximating line can be controlled by electrical s)imulation of the contralateral forepaw8 The aim of the present study is to extend our description of the modulating influence of peripheral signals on the central VL-MC system including visual and auditory inputs as well as somesthetIc METHODS Experiments were performed on 20 adult, female cats, weighing from 2 to 3 kg In all 20 cases, peripheral signals were introduced by electrical stimulation of the contralatereal forepaw. In 5 of the 20 cases visual and auditory stimuli were also employed Each animal was anesthetized by intravenous injection of sodium pentobarbital (30 mg/kg) with supplemental doses given when needed A detmled methodology, covering the surgical procedures, the thalamlc stimulation techniques and the cortical recording and analysis methods, has recently been described7, therefore, only those details related to peripheral stimulation are discussed in depth. The thalamlc electrode, through which rectangular pulses of 1 msec duration were delivered, either singly or In closely spaced (70-130 msec) pairs, was stereotaxIcally placed in the right ventrolateral nucleus Cortical evoked slow-wave responses were measured * Present address BlornedlcalEngmeenng,Johns HopkansUmvers~ty,BalUmore,Md 21205,U S A Brain Research, 38 (1972) 35--47
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R N JOHNbON AND G R HANNA
by a 20 contact, flexible, printed c~rcult recording array 6 which completely covered the r~ght slgmold gyli Responses were amplified, d~splayed on a cathode ray oscilloscope and recorded photographically A peripheral stimulus was timed to either lead, lag or coincide with a thalam~c conditioning stimulus The time between the peripheral and central stlmuh, designated as the peripheral-central time difference (X), was considered to be the major peripheral input variable The peripheral signal was originated by a visual flash, auditory click or electrical stimulus to the contralateral forepaw The peripheral electrical stimulus (1 msec duration) was delivered to the left forelimb wa two 25gauge needle electrodes, which were placed either into the skin on the superior surface of the forepaw or into the central footpad, to activate cutaneous afferent fibers of the paw 11 The level of anesthesm was maintained such that hard pinching of the forepaw produced a slight movement The amplitude of the l~erlpheral electrical stimulus was increased to a point just above wrist movement threshold (5-10 V) as indicated by a sensitive transducer attached to the forepaw The peripheral cortical evoked response measured from the lateral slgmold gyrus was also observed, however, movement threshold was judged to be the simplest, reproducible standard by which to set peripheral electrical stimulus amphtude The time delay between the peripheral electrical stimulus and the beginning of the cortical evoked response (5-10 msec) was compared to the delay to onset of limb movement (15-20 msec) The visual stimulus consisted of a binocular light flash dehvered via a Grass PS-1 photo stimulator An electronically driven mechanical relay, which was rigidly fixed to the stereotaxlc instrument frame, was used to dehver bilateral chcks through sohd ear bars No simple standard such as movement threshold was available to judge the amphtudes of the visual and auditory stimuli The sufficiency of the auditory and visual stimulus levels to influence the V L - M C system was judged during subsequent data analysis At the termination of each experiment, electrode locations were marked by electrolytic deposition of iron trom both thalamlc and cortical electrodes The location of the thalamlc electrode was subsequently confirmed histologically RESULTS
Input-output relatzons In order to test any machine we must first identify the input(s) and the output(s) In addition to this we must consider the state of the machine at the time of our test. For if the machine changes its state, the output will be different for identical inputs 7. We have previously shown that the thalamocortlcal motor system does exhibit state changes which can be brought about by response repetition 7,8 or by peripheral signals s In this study we have adopted the viewpoint that the input-output relataonshlp defined for the central V L - M C system can be changed by signals arriving from the periphery It is the peripheral signal which controls, in part, the state of the central neuronal machine F~g IA shows, m schematic form, the response measured on cat sensonmotor Brain Research, 38 (1972) 35-47
THALAMOCORTICAL SYSTEM
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Fig 1 Varlablesassocmtedwithevokedresponsepuisepalrs A, Schematic representatlon of response measured on cat sensonmotor cortex following ventrolateral (VL) stimulation C o n d m o n m g sUmuh ($1) are dehvered to VL at a 1/sec rate The time interval from the condmonlng stimulus ($1) to the beginning of the afterdlscharge is termed the clock time (C) Test stimuh ($2) are delivered within the C interval to VL for various pulse pmr intervals (t) Sensory information (SI) is introduced via a peripheral signal m the form of a visual flash, auditory chck or electrical pulse to the contralateral forepaw Sensory input IS timed to esther lead, lag or comode with the condmonlng stimulus The time between the peripheral stimulus and the central stimulus is termed the peripheral-central time difference (X) with positive X implying central stimulus lead B, Simplified concept of the V L - M C system illustrating that a change in machine output (AY), which is defined for the test response, is related to a change in the pulse pmr interval (At) by the parameter R The system parameter R is controlled by sensory input (SI) C, Typical evoked responses obtained from test stlmuh ($2) dehvered for t = 85 msec Waveform 2 was obtained after the contralateral brachlum conjunctwum (BC) was destroyed by electrocoagulatlon When machine output is defined for the initial peak (Yp), httle difference exists between waveforms 1 and 2 When an area measure for machine output (Ya) is used, based on a 20 msec interval, slgntficant change ~s noted between waveforms 1 and 2 Posmvity upwards
cortex (MC) following electrical stimulation of ventrolateral thalamus (VL) Numerous responses which support this &agram have been previously published7, s When a conditioning stimulus ($1) IS dehvered to VL, an lnmal surface positive response of about 10-25 msec duration will occur, followed m about 150msec by a largely negatwe after&scharge We have previously defined the time interval from the first stimulus to the beginning of the after&scharge as the clock time (C)7, s It is wtthm this interval C that test stlmuh ($2) will be dehvered to VL for various pulse pair intervals (t), since this has been shown to be the interval over which response change occurs 7,s The central input variable is then defined as the pulse pair interval (t) and an output measure will be defined m the following paragraphs for the second response of the pair (test response) When the test stimulus ($2) is dehvered, the afterdlscharge is delayed and does not occur until approximately 150 msec after the test stimulus 7,s Bram Research, 38 (1972) 35-47
38
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In order to contend w i t h changing machine states due to response repetition, we have developed the following routine 7,8 F~rst, a single stimulus ($1) ~s dehvered to VL and the normal afterdlscharge is allowed to occur Then, one second later, a pulse pair is delivered at some t value This procedure ot delivering a single pulse (SP) and one second later a pulse pair (DP) is then repeated for all t <~C This method is termed an S P - D P non-sequential test as opposed to a sequential test where pulse pairs are delivered at 1/sec intervals Consider the case where a peripheral signal, either wsual, auditory, or somesthetic, is sent m to change the state of the neuronal machine The sensory information (SI) is then timed to either lead, lag or coincide with the first VL stimulus ( F i g 1A) The time difference between the central stimulus and the peripheral stimulus is termed the peripheral-central time difference (X) with poSltlVe X values denoting central stimulus lead The S P - D P nonsequentml test is then conducted for a constant X value In actual practice, we dehver 4 SI-SI pairs at a 1/sec rate The thalam~c test stimulus ($2) is dehvered after the second SI-SI pair for a fixed t value The third and fourth S1-SI pmrs occur alone w~thout any test stimulus being delivered This procedure is then repeated for a different t value but for the same X value N o w let us return to the problem of determining a measure of machine output. A typical evoked response obtained from a test stimulus delivered for a t value of 85 msec is shown in Fig 1C1 The response is i n i t i a l l y s u r f a c e p o s i t i v e and resembles a damped oscillation In previous experiments 7,a we have used an average value, obtained by taking the area enclosed by the curve (Fig 1C, shaded area) over a 20 msec Interval and divided by the interval chosen, as an index o f machine output (Ya) An alternative measure of machine output would be to measure the peak amplitude of the Imtlal p o s i t i v e response (Yp) Fig 1C1 w a s obtained from the same case as A
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Fig 2 Nonsequentlal test showing the change m machine output (Y) as a function of the pulse pair interval (t) N o sensory input used Each data point represents the mean ± S E M of 7 measurements A hnear approximation of the data has been assumed over a restricted range of t values (70-130 msec) The sohd hne was obtained by least squares analysis, with the slope of the line defined as the central rate sensmvlty (R) The dashed hnes Indicate the nonhnear regions Case N o 303 A, The peak measure for calculating machine output (Yp) has been used The product-moment correlation coefficient is 0 969 B, Same data as plotted in A with the area based measure used for calculating machine output (Y~) The product-moment correlation coefficient is 0 982
Bram Research, 38 (1972) 35-47
THALAMOCORTICALSYSTEM
39
Fig 1C2 and for the same t value (85 msec) Although the peak amphtude of the mmal positive response is Identical for both cases, the area enclosed by the curve has more than doubled m waveform 2 over 1 Waveform 2 (Fig 1C) was obtained after the contralateral brachlum conjunctwum (BC) was destroyed by electrocoagulatlon For the experiments illustrated in th~s paper, we wdl demonstrate that using the measure of initial peak (Yp), we obtained the same results as using the area definition (Ya) However, in any experiment where BC is opened or cerebellar influences are being studied, differences wdl become apparent between the two measures Machine output (Y) plotted as a function of the pulse pair Interval (t) is shown m Fig 2 (case No 303) In Fig 2A the peak measure (Yp) is used whereas m Fig 2B the same data are plotted using the area measure (Ya) Each data point represents the mean 4- S E M of 7 values Note that for t values between 70 msec and 130 msec the input-output relationship is approximately hnear, with the sohd hne (Fig 2) obtained by the method of least squares The product-moment correlation coefficient is 0 982 for Fig 2B using the area measure and slightly less (0 969) in Fig 2A using the peak measure The dashed lines illustrate the range of t values where the system becomes nonhnear A description of the response profile over an extended range of t values (50-250 msec) has been previously reported7, s In the hnear region between t = 70 and t : 130 msec the system can be approximated by the relation Y = R t q- K (in #V) relating the pulse pmr interval (t) m msec to the machine output (Y) in m~crovolts The slope of the hne we have termed central rate sensitivity (R), with the subscripted parameter Ra implying the area method for machine output ~s being used and Rp implying that the peak measure Is being used In the following illustrations we will show that the system parameter R can be varwd by peripheral signals This point is summarized m the diagram of Fig 1B where a change m machine output (AY) is related to a change m the pulse pair interval (At) by the system parameter R, with R being controlled by sensory input
Sensory control In order to demonstrate sensory control of the system parameter R, we conduct an S P - D P nonsequentlal test for a fixed X value We assume that a hnear approxamatlon is adequate over a range o f 7 equally spaced (10 msec) t values from 70 to 130 msec By using least squares analysis, we can then obtain an R value for a specific X Fig 3 illustrates central rate sensitivity (R) plotted as a function o f the peripheralcentral time difference (X) for case No 292, with Fig 3A showing R obtained by using the peak measure for machine output and with Fig 3B derived from the same data using the area measure. Both Fig 3A and B demonstrate that minimum R occurs at X = 0 and also that a second reduction in R occurs at X = + 7 5 msec The peripheral signal for this case (No 292) was a cutaneous electrical stimulus dehvered to the contralateral forepaw
Brain Research,38 (1972) 35~.7
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Fig 3 The relatton between central rate sensmvlty (R) and the peripheral-central time difference (X) when a random sequence of X values has been employed Note that minimum R occurs at X = 0 The product-moment correlation coefficient is m&cated for each R value The peripheral signal was originated by a cutaneous electrical snmulus dehvered to the contralateral forepaw The normal value obtained w~thout peripheral st~mulatlon is indicated by the arrow on the vertical axis The cortical recording site is indicated just anterior to and at the lateral end of the crucmte sulcus Case No 292 A, The peak measure for machine output (Yp) has been used to calculate Rp B, The area based measure for machine output (Ya) has been used to calculate Ra from the same data as used m A Note that the response profile is slmdar to that shown m A
W e have previously indicated that the sequence o f dehvery o f X values can also lnfluence the R parameter s For this reason the data o f Fig 3 were collected using a sequence w h i c h was determined by r a n d o m draw (X ---- - - 5 0 , no peripheral input, - - 1 0 0 , 6.100, 6.150, - - 1 5 0 , 6-50, 6-75, --25, 0, --75, 6-25) A single d e m o n -
stratlon is, of course, not sufficient to demonstrate that the minimum will rehably occur at R (X = 0), where R(X = 0) is read as 'the value of R at X = 0' A second test was conducted on this preparaUon ( N o 292) 30 mm later, following a different sequence, again determined by random draw (X = 6-25, 6" 100, --150, --100, --50, no peripheral input, --75, 0, 6-75, --25, 6-50, 6-150) The form of the response was virtually ldenUcal with the minimum R occurring at X = 0 and a second reduction at X = 6-75 msec (ref 8, Fig 6) The product-moment correlation coefficients are indicated adjacent to each data point in Fig 3 On the basis of the correlation coefficients there is no reason to state that the area measure of machine output is greatly superior to the peak measure In both cases the correlation coefficients drop as the slope (R value) of the approximating line is reduced This, of course, is to be expected Several examples o f this line rotation have been given previously a, where the R value changed from 2 5 / z V / m s e c to 0 3 5 / ~ V / m s e c and the correlation coefficient dropped from 0 98 to 0 62 (ref 8, Fig 4 A and B) It should be noted that each data point s h o w n in Fig 3
was obtained by fitting a line to 7 machine output values, equally spaced (10 msec) from t -- 70 to t = 130 msec, and is not an average of 7 tests as demonstrated in Fig 2 The small brain diagram m the center o f Fig 3 m & c a t e s the cortical recording
site for the data displayed Bram Research, 38 (1972) 35-47
41
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Fig 4 The relationship between central rate sensitivity (R) and the peripheral--central time difference (X) when the peripheral signal has been originated by a binocular light flash A, The peak measure for machine output has been used Plot 1 was obtained by a symmetrical X sequence Plot 2 (dashed line) was obtained immediately after 1 utilizing a random sequence of X values Minimum R occurs at X = 0 in both cases The cortical recording site is represented by the open circle Case No 301 B, The area based measure for machine output (Y~) has been used to calculate Ra with a symmetrical X sequence being employed Again minimum R occurs at X = 0 The cortical recording site is represented by the filled circle Case No 300
Consider now the case illustrated in Fig 4 where visual signals (binocular light flash) were used to control R values In Fig 4A (case No 301) the peak measure for machine output has been used Fig 4A1 was obtained by using a symmetrical sequence of X values (X ---- dz 25, + 50, 0, --50, ± 100) In Fig 4A2 a second test was conducted immediately following the first using a r a n d o m sequence of X values (X ---- + 2 5 , --75, 0, --25, + 7 5 , + 5 0 , +100, --100, - - 5 0 ) With the exception of the values for R (X ---- + 2 5 ) both results take the same form with a minimum at R (X ----0) Note that both the symmetrical and random sequence started with X ---- + 2 5 msec. The area measure for machine output (Ya) has been used in Fig 4B, case N o 300, with visual input and a symmetrical presentation ( ± 2 5 , + 5 0 , 0, --50, ± 7 5 , -t-100) Minimum R again occurs at X ---- 0 with a second reduction in the X = + 5 0 to X = + 7 5 msec range The brain diagram in the center of Fig 4 indicates the cortical recording site with case N o 301, represented by the open circle, being slightly anterior to case No 300 (filled circle) Let us turn now to the situation when auditory signals (bilateral clicks, see Methods) are used (Fig 5, case No 302) In Fig 5A the peak measure for machine output has been used, with X values presented in symmetrical fashion ( ± 2 5 , + 5 0 , 0, --50, -4-100, :El50) Note that our 'tuning curve' is not as sharp as in Fig 3 with R (X = 0) and R (X = - - 5 0 ) both reduced Fig 5Ba shows the same data as in A but derived from the area measure for machine output Again, curve 1, Fig 5B shows the same broad minimum as in Fig 5A Curve 2, Fig 5B, was derived from the area measure and conducted immediately after curve 1 but in the reverse sequence (X ---= ZF 150, T 100, --50, 0, + 5 0 ) Note in Fig 5B curve 1, the sequence about zero was X -----+50-+X = 0-+X = --50, whereas in curve 2 the reverse sequence was used Brain Research, 38 (1972) 35-47
42
R N JOHNSON AND G R HANNA
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Fig 5 The relationship between central rate sensitivity (R) and the peripheral-central time difference (X) when the peripheral signal has been originated by a bilateral click The cortical recording site is represented by the filled circle Case No 302 A, The peak measure for machine output has been used with X values presented m symmetrical sequence Note the broad minimum extending from X = 0 lo X = - - 5 0 msec The arrows indicate the X sequence about zero (X = + 50 -~ X = 0 -7 X = --50) B, The area measure for machine output has been used to calculate Ra (plot 1) from the same dala as used m A Plot 2 (dashed line) was obtained immediately after 1, using a reverse sequence of X values The arrows indicate the X sequence about zero for each plot Note the X sequence sensitw ty of the R (X = 0) value
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Fig 6 The relationship between central rate sensitivity (R) and the peripheral-central time difference (X) when the peripheral signal has been originated by an electrical stimulus delivered to the central footpad of the contralateral forepaw The peak measure for machine output has been used to calculate Rp The cortical recording site is represented by the filled circle Case No 304 A, Plot 1 was obtained by starting from the left (X = --150) and moving to the right (X = +150) Plot 2 was then obtained by starting from the right (X = + 150) and moving to the left (X = --150) Note the hysteresis effect m the victmty of X = 0 B, The procedure listed m A above was repeated Again note the hysteresis effect m the VlClmty of X = 0
Bram Research, 38 (1972) 35--47
THALAMOCORTICAL SYSTEM
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(X = - - 5 0 - + X = 0-+X = 4 5 0 ) T h e greatest difference between curve 1 a n d 2 occurs at X = 0 W e c a n see t h a t the X sequence a p p e a r s to influence o u r results, p a r t i c u l a r l y at X = 0, the very p o i n t we c l a i m e d in F i g s 3 a n d 4 to p r o d u c e m i n i m u m R values. O f course, in n o n e o f the p r e v i o u s figures have we illustrated a s y m m e t r i c a l sequence which started w~th X = - - 1 5 0 msec It is i m p o r t a n t to note in F i g 5B t h a t in the vxcinity o f X -----0, f o r curve 2, we are a p p r o a c h i n g f r o m the right--1 e , X = + 100 a n d t h e n - - 5 0 ~ 0 - + + 5 0 - - - a n d m curve 1 we a p p r o a c h f r o m the l e f t - - t e , X = - - 2 5 a n d then 4 5 0 - + 0 > 50 T h e b r a i n d i a g r a m in the center o f F i g 5 indicates the cortical r e c o r d i n g site which, for this case ( N o 302), was medial to all p r e v i o u s examples A s y m m e t r i c a l sequence ~s n o t the best w a y to c o n s i d e r d i r e c t i o n sensltIwty as we are c o n t i n u a l l y a l t e r n a t i n g in a p p r o a c h d i r e c t i o n (sign o f X) F i g 6 illustrates 4 tests c o n d u c t e d o n a single a n i m a l ( N o 304) with two tests (solid lines) starting f r o m the left ( X = - - 1 5 0 ) a n d m o v i n g t o w a r d the right (X = + 150) a n d two tests ( d a s h e d lines) starting f r o m the right (X = + 150) a n d m o v i n g to the left (X = - - 1 5 0 ) T h e p e r i p h e r a l signal f o r this case ( N o 304) was delivered w a an electrical stimulus to the central f o o t p a d o f the c o n t r a l a t e r a l f o r e p a w T h e p e a k m e a s u r e for m a c h i n e o u t p u t was used In F i g 6 to calculate central rate s e n s m w t y (Rp) C u r v e 1, F i g 6 A was o b t a i n e d first, then curve 2, F i g 6 A The d a t a for curve 1, F i g 6B were then o b t a i n e d , f o l l o w e d b y curve 2, F i g 6B It t a k e s a p p r o x i m a t e l y 17 min to collect sufficient d a t a to calculate 11 R values (1 5 m m / R value), hence the d a t a d i s p l a y e d in F i g 6 represent 1 h o f testing N o t e in F i g 6A1, as we a p p r o a c h f r o m the left the R value d r o p s at X = - - 2 5 msec a n d r e m a i n s a t t e n u a t e d at X = 0 a n d then m o v e s b a c k to a h~gher value again at X = 4 2 5 msec W h e n we a p p r o a c h f r o m the right, R values r e m a i n high t h r o u g h the X = 0 p o i n t a n d t h e n d r o p at X = - - 2 5 msec This p r o d u c e s a hysterems
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Fig 7 The rel&t]onshlpbetween central rate sensmvlty (R) and the peripheral-central time difference (X) as obtained by averaging Each data point represents the mean :E S E M of 4 values, each of which were mdwldually plotted m Fig 6 Note that minimum R occurs at X = --25 msec However, the standard error of the mean is nearly twice as large at X = 0 than for any other X value since R (X = 0) is influenced by the dlrectmn of approach to X = 0 (Fig 6) Bram Research, 38 (1972) 35-47
44
R N JOHNSON AND G R HANNA
effect in the vicinity of X -- 0 This phenomenon is also demonstrated in Fig 6B, with the hysteresis effect m the WClmty of X =- 0 easier to observe since the R values outside the ± 5 0 msec range have not drifted apart as in Fig 6A The mean ~_- S E M (n = 4) of each R value from the 4 tests shown in Fig 6 is plotted in Fig 7 Note that the standard error of the mean is nearly twice as large at the X -- 0 point than for any other X value It is clear from Figs 5B and 6 that the prior sequence of X values determines whether R (X 0) assumes a high or low numerical value We believe the V L - M C system can be considered, in part, as a direction sensitive null detector with the peripheral-central time difference (X) being the input variable to which the neuronal machine responds For the case shown in Fig 6 the minimum or null point occurs at X = - - 2 5 msec when we approach from the right and is somewhat broader, covering the range from X = --25 to X =- 0, when we approach from the left The brain diagram in Fig 6 (case No 304) indicates that the cortical recording site w a s j u s t anterior to the lateral end of the cruclate sulcus DISCUSSION
Our general approach has been to consider the central input-output relationship, characterized by the parameter R, to be a reflection o f the state of the V L - M C system We have taken the viewpoint that it is the peripheral signal, impinging on the central processor, that brings about a change in the state of the system We have chosen to obtain R for a fixed peripheral-central time difference (X) and then illustrate R changes as a function of X It is important to stress that we have considered only the information contained in the time difference between the peripheral and the central stimulus In this respect, the V L - M C system does not appear to differentiate between sensory modahtles and will respond to the peripheral-central time difference irrespective of the source and site of Initiation of the peripheral signal The results one obtains from experiments of this kind are, of course, determined by the variables selected as measures of Input and output and the experimental pretocol employed In this paper we have Illustrated two methods of measuring machine output One method measured peak response and the second was an area based measure taken over a 20 msec interval Both measures produce similar representations of machine performance As we pointed out in Fig 1C, such would not be the case where, by experimental design, we open the contralateral brachlum conjunctlvum, for then wide differences between the peak and area based measures would appear A major question to consider is what inherent capability, as a dynamic signal processor, does the cat thalamocortlcal motor system have As such, a single cortIcal response has little meaning, for we are looking for a change In cortical response which is related to a change m the input The parameter termed the central ra~e sensitivity (R) relates the change in machine output ( A y ) to a change in the input (pulse pair interval, At) The R value becomes a measure of the state of the system The R parameter follows from the assumption that the system is approximately linear for t values from 70 to 130 msec The R parameter, which we say reflects the state of the system, was found to be a function of the peripheral--central time difference (X) From the results
Bram Research, 38 (1972) 35-47
THALAMOCORTICAL SYSTEM
45
shown in Figs 3-7 we conclude that the V L - M C system can perform as a null detector or signal coincidence detector That is, as the peripheral and central stlmuh move toward correspondence the R parameter moves to a minimum value The null point occurs at X = - - 2 5 msec (peripheral signal leads central by 25 msec) for the case shown m Fig 6 with the value for R(X ----0) being either high or low depending on the previous sequence of X values dehvered The V L - M C system has the capability to perform as a null detector whose ultimate response profile is dependent on the sequence of X values employed Asanuma et al 1 have suggested that afferent inputs from restricted peripheral loci 'reflexly' induce muscle contraction through a loop including motorsensory cortex, and they cite as an example the wellknown 'tactile placing reaction' m the cat It has been further suggested by Asanuma et al 1 that cutaneous input may serve as feedback information during a pursuit movement Elements of both of these suggestions have been incorporated into our experimental design We have maintained the amplitude of the peripheral stimulus delivered to the contralateral forepaw at a level just sufficient to produce wrist movement The timing between the peripheral stimulus and the central stimulus then forms that quantity of information which we have termed the peripheral-central time difference (X) As discussed above, the dynamics of the central system, as characterized by the parameter R were shown to be a function of X We can understand that cutaneous input may well serve as feedback information during a complex pursuit movement However, more sophisticated test protocols must be devised, considering visual, auditory and somesthetlc inputs, in order to delineate the underlying central dynamics associated with complex movements We have previously shown that the V L - M C system forms a 'self-modifying' machine, l e , a machine whose cortical response is due to both incoming information and information i r o m its past history of use 7,8 This influence from the past IS again evident in the hysteresis phenomenon about X = 0, as demonstrated in Figs 5B, 6 and 7 We feel that any protocol devised to test the V L - M C system must always consider the state of the system as determined by its past history, in addition to Incoming information (input) as the determinants of the response (output) Our 'black box' methods of manipulating Inputs and measuring outputs are designed to demonstrate the dynamic performance capabilities of the V L - M C system and not to extract information about the internal 'parts' (neurons, etc ) within the box Creutzfeldt et al 5 show an average IPSP of a cortical cell following 1/sec ventrolateral stimulation Inspection of their data (ref 5, Fig 10C) shows that the IPSP plotted as a function of time is approximately linear in the range from 70 to 130 msec after the stimulus It seems reasonable to assume that the approximate hnearity of the IPSP versus time plot is reflected in the linear relation that we have shown in Fig 2 We do not know at this time whether the slope of the IPSP versus time curve can be shown to be a function of the peripheral-central time difference (X) There is little doubt that cat pericruclate corCex receives a wide range of sensory inputs1,2,4,11,12,14-10 with m a n y neurons, primarily in precruclate tissue, being polysensory 11 Quant~tatlve functional relationships between variables describing the thalamocort~cal m o t o r system at the neuronal level remain to be developed It is our belief that an underBram Research, 38 (1972) 35-47
46
R N JOHNSON AND G R HANNA
standing of the dynamic relationships of large neuronal aggregates will prowde gmdehnes for further quantltatwe studtes at the neuronal level Differences at the neuronal level between precrucmte and postcrucmte cortex have recently been summarized by Nyqmst and Towe 11 All of the data reported m our study were obtained from a cortical recording site either lmmedmtely anterior to or at the lateral end of the crucmte sulcus In 10~o of the cases studied we have successfully recorded from postcrucmte tissue It is possible to control, at least by electrical stimulation of the contralateral forepaw, the R parameter derived from measurements taken from postcruclate t~ssue The response profile ~s similar to that reported here, but the null point is shifted to the left m the range of X ------ - 5 0 to X = --75 msec (ref 8, Fig 5B) SUMMARY
A hnear approximation of the input-output relatmnshlp between ventrolateral (VL) nucleus and sensorlmotor cortex (MC) in the cat has been employed The slope of the transfer function has been termed the central rate sensltwlty (R) It has been shown that the system parameter R can be controlled by the time interval between a central thalam~c stimulus and a peripheral stimulus, e~ther auditory, visual or somesthetlc The response profile of the system, plotting central rate sensmwty (R) as a function of the peripheral-central time difference (X) indicates that the V L - M C system can perform as a null detector, w~th minimum R values occurring m the vicinity of peripheral-central signal correspondence The system shows considerable hysteresis m the regmn of X = 0 with the value for R(X = 0) determmed by the dlrecUon of approach toward X -~ 0, where the term direction lmphes a lead or lag relationship between the peripheral and central stimulus ACKNOWLEDGEMENTS This research was supported m part by grants from U S Pubhc Health Service (No F3-Gm-35,680 and NB 05120) and Social and Rehabdltatlon Service, Department of Health, Education and Welfare (No R D 1870-M) We are mdebtexi to Mrs Sharon Trader for her technical assistance
REFERENCES 1
ASANUMA, H , STONEY, S
D, JR, ANDAaZUG,C, Relationship between afferent input and motor outflow m cat motorsensory cortex, J Neurophyslol, 31 (1968) 670-681 2 BROOKS,V B, Information processing m the motorsensory cortex In K N LEIBOVIC(Ed), Information Processing m the Nervous System, Spnnger, New York, 1969, pp 231-243 3 BUSER,P, Subcortlcal controls of pyramidal acUwty In D P PURPURAANDM D YAHR(Eds), The Thalamus, Columbia Umv Press, New York, 1966, pp 323-344 4 BusEs, P, AND IMB~RT,M, Sensory projectmns to the motor cortex m cats A mlcroelectrode study In W A ROSl/NSLITH(Ed), Sensory Commumcatton, Wdey, New York, 1961, pp 607-626 5 CREUTZFELDT, O D , LUX. H D , AND WATANABE, S , Electrophystology of cortical nerve cells. Brain Research, 38 (1972) 35-47
THALAMOCORTICAL SYSTEM
6 7
8 9 10 11 12 13 14
15
16
47
In D P PURPURA AND M D YAHR (Eds), The Thalamus, Columbia U m v Press, New York, 1966, pp 209-230 HANNA, G R , AND JOHNSON, R N , A rap~d and simple method for the fabrication of arrays of recording electrodes, Electroenceph din Neurophystol, 25 (1968) 284-286 JOHNSON, R N , AND HANNA, G R , The thalamocortlcal system as a neuronal machine the interaction of ventrolateral nucleus with sensonmotor cortex m the cat, Brain Research, 18 (1970) 219-239 JOHNSON, R N , ANt) HANNA, G R , An elementary description of thalamocort~cal system dynamics m the cat, Brain Research, 31 (1971) 119-137 MOUNTCASTLE, V B , AND HENNEMAN, E , Pattern of tactile representation in thalamus of cat, J Neurophyslol, 12 (1949) 85-100 MOUNTCASTLE, V B , POGGIO, G F , ANt) W~RNER, G , The relation of thalamlc cell response to peripheral stlmuh varied over an intensive continuum, J Neurophyslol, 26 (1963) 807-834 NYQUIST, J K , AND TOWE, A L , Neuronal activity evoked m cat precruclate cerebral cortex by cutaneous stimulation, Exp Neurol, 29 (1970) 494-512 OSCARSSON, O , AND ROS~N, I , Short-latency projections to the cat's cerebral cortex from skin and muscle afferents m the contralateral forelimb, J Physwl (Lond), 182 (1966) 164-184 Poc~3IO, G F , ANt) MOUNTCASTLE, V B , The functional properties of ventrobasal thalamlc neurons studied m unanesthetized monkeys, J Neurophystol, 26 (1963) 775-806 TOWE, A L , PATTON, H D , ANt) KENNEDY, T T , Response properties of neurons m the pen. crucmte cortex of the cat following electrical shmulation of the appendages, Exp Neurol, 10 (1964) 325-344 WELT, C , ASCHOFF, J C , KAMEDA, K , AND BROOKS, V B , Intracortlcal organization of cat's motorsensory neurons In M D YAHR, AND D P PURPURA (Eds), NeurophyswlogwalBasts of Normal and Abnormal Motor Actlvmes, Raven Press, Hewlett, N Y , 1967, pp 255-288. WHITEHORN, D , AND TOWE, A L , Postsynapt~c potentml patterns evoked upon cells m sensonmotor cortex of cat by stimulation at the periphery, Exp Neurol, 22 (1968) 222-242
Brain Research, 38 (1972) 35-47
35
MODULATION OF THE THALAMOCORTICAL MOTOR SYSTEM BY SENSORY INFORMATION
R N JOHNSON* ANDG R HANNA Department of Neurology, Umverstty of Vtrgmla School of Medicine, Charlotteswlle, Va 22901 (usa)
(Accepted September 3rd, 1971)
INTRODUCTION Numerous investigators have studied the influence of peripheral signals on both thalamlc structuresa,9,10,1a and single neurons within sensorimotor cortex1,2,4,14-1e The polysensory nature of cat sensorImotor cortex, particularly precruciate tissue, has been shown, responding to light, sound and somatic inputs 11 We have previously considered the dynamic aspects of the ventrolateral (VL) thalamic-sensorlmotor (MC) cortical system from the more general Input-output viewpoint7,s We have recently shown that the VL-MC system in the cat can be consldered to be approximately linear over a restricted range of responses and that the slope of the approximating line can be controlled by electrical s)imulation of the contralateral forepaw8 The aim of the present study is to extend our description of the modulating influence of peripheral signals on the central VL-MC system including visual and auditory inputs as well as somesthetIc METHODS Experiments were performed on 20 adult, female cats, weighing from 2 to 3 kg In all 20 cases, peripheral signals were introduced by electrical stimulation of the contralatereal forepaw. In 5 of the 20 cases visual and auditory stimuli were also employed Each animal was anesthetized by intravenous injection of sodium pentobarbital (30 mg/kg) with supplemental doses given when needed A detmled methodology, covering the surgical procedures, the thalamlc stimulation techniques and the cortical recording and analysis methods, has recently been described7, therefore, only those details related to peripheral stimulation are discussed in depth. The thalamlc electrode, through which rectangular pulses of 1 msec duration were delivered, either singly or In closely spaced (70-130 msec) pairs, was stereotaxIcally placed in the right ventrolateral nucleus Cortical evoked slow-wave responses were measured * Present address BlornedlcalEngmeenng,Johns HopkansUmvers~ty,BalUmore,Md 21205,U S A Brain Research, 38 (1972) 35--47
36
R N JOHNbON AND G R HANNA
by a 20 contact, flexible, printed c~rcult recording array 6 which completely covered the r~ght slgmold gyli Responses were amplified, d~splayed on a cathode ray oscilloscope and recorded photographically A peripheral stimulus was timed to either lead, lag or coincide with a thalam~c conditioning stimulus The time between the peripheral and central stlmuh, designated as the peripheral-central time difference (X), was considered to be the major peripheral input variable The peripheral signal was originated by a visual flash, auditory click or electrical stimulus to the contralateral forepaw The peripheral electrical stimulus (1 msec duration) was delivered to the left forelimb wa two 25gauge needle electrodes, which were placed either into the skin on the superior surface of the forepaw or into the central footpad, to activate cutaneous afferent fibers of the paw 11 The level of anesthesm was maintained such that hard pinching of the forepaw produced a slight movement The amplitude of the l~erlpheral electrical stimulus was increased to a point just above wrist movement threshold (5-10 V) as indicated by a sensitive transducer attached to the forepaw The peripheral cortical evoked response measured from the lateral slgmold gyrus was also observed, however, movement threshold was judged to be the simplest, reproducible standard by which to set peripheral electrical stimulus amphtude The time delay between the peripheral electrical stimulus and the beginning of the cortical evoked response (5-10 msec) was compared to the delay to onset of limb movement (15-20 msec) The visual stimulus consisted of a binocular light flash dehvered via a Grass PS-1 photo stimulator An electronically driven mechanical relay, which was rigidly fixed to the stereotaxlc instrument frame, was used to dehver bilateral chcks through sohd ear bars No simple standard such as movement threshold was available to judge the amphtudes of the visual and auditory stimuli The sufficiency of the auditory and visual stimulus levels to influence the V L - M C system was judged during subsequent data analysis At the termination of each experiment, electrode locations were marked by electrolytic deposition of iron trom both thalamlc and cortical electrodes The location of the thalamlc electrode was subsequently confirmed histologically RESULTS
Input-output relatzons In order to test any machine we must first identify the input(s) and the output(s) In addition to this we must consider the state of the machine at the time of our test. For if the machine changes its state, the output will be different for identical inputs 7. We have previously shown that the thalamocortlcal motor system does exhibit state changes which can be brought about by response repetition 7,8 or by peripheral signals s In this study we have adopted the viewpoint that the input-output relataonshlp defined for the central V L - M C system can be changed by signals arriving from the periphery It is the peripheral signal which controls, in part, the state of the central neuronal machine F~g IA shows, m schematic form, the response measured on cat sensonmotor Brain Research, 38 (1972) 35-47
THALAMOCORTICAL SYSTEM
A
37
1 Sec
F SI
-X
+X
k/ Sl(VL)
B
5 (VL)
sI
SI
S2(VL)
C ''Ya
t I SI
S2 T=20msec
S2
Fig 1 Varlablesassocmtedwithevokedresponsepuisepalrs A, Schematic representatlon of response measured on cat sensonmotor cortex following ventrolateral (VL) stimulation C o n d m o n m g sUmuh ($1) are dehvered to VL at a 1/sec rate The time interval from the condmonlng stimulus ($1) to the beginning of the afterdlscharge is termed the clock time (C) Test stimuh ($2) are delivered within the C interval to VL for various pulse pmr intervals (t) Sensory information (SI) is introduced via a peripheral signal m the form of a visual flash, auditory chck or electrical pulse to the contralateral forepaw Sensory input IS timed to esther lead, lag or comode with the condmonlng stimulus The time between the peripheral stimulus and the central stimulus is termed the peripheral-central time difference (X) with positive X implying central stimulus lead B, Simplified concept of the V L - M C system illustrating that a change in machine output (AY), which is defined for the test response, is related to a change in the pulse pmr interval (At) by the parameter R The system parameter R is controlled by sensory input (SI) C, Typical evoked responses obtained from test stlmuh ($2) dehvered for t = 85 msec Waveform 2 was obtained after the contralateral brachlum conjunctwum (BC) was destroyed by electrocoagulatlon When machine output is defined for the initial peak (Yp), httle difference exists between waveforms 1 and 2 When an area measure for machine output (Ya) is used, based on a 20 msec interval, slgntficant change ~s noted between waveforms 1 and 2 Posmvity upwards
cortex (MC) following electrical stimulation of ventrolateral thalamus (VL) Numerous responses which support this &agram have been previously published7, s When a conditioning stimulus ($1) IS dehvered to VL, an lnmal surface positive response of about 10-25 msec duration will occur, followed m about 150msec by a largely negatwe after&scharge We have previously defined the time interval from the first stimulus to the beginning of the after&scharge as the clock time (C)7, s It is wtthm this interval C that test stlmuh ($2) will be dehvered to VL for various pulse pair intervals (t), since this has been shown to be the interval over which response change occurs 7,s The central input variable is then defined as the pulse pair interval (t) and an output measure will be defined m the following paragraphs for the second response of the pair (test response) When the test stimulus ($2) is dehvered, the afterdlscharge is delayed and does not occur until approximately 150 msec after the test stimulus 7,s Bram Research, 38 (1972) 35-47
38
R
N
IOHNSON
AND
G
R
HANNA
In order to contend w i t h changing machine states due to response repetition, we have developed the following routine 7,8 F~rst, a single stimulus ($1) ~s dehvered to VL and the normal afterdlscharge is allowed to occur Then, one second later, a pulse pair is delivered at some t value This procedure ot delivering a single pulse (SP) and one second later a pulse pair (DP) is then repeated for all t <~C This method is termed an S P - D P non-sequential test as opposed to a sequential test where pulse pairs are delivered at 1/sec intervals Consider the case where a peripheral signal, either wsual, auditory, or somesthetic, is sent m to change the state of the neuronal machine The sensory information (SI) is then timed to either lead, lag or coincide with the first VL stimulus ( F i g 1A) The time difference between the central stimulus and the peripheral stimulus is termed the peripheral-central time difference (X) with poSltlVe X values denoting central stimulus lead The S P - D P nonsequentml test is then conducted for a constant X value In actual practice, we dehver 4 SI-SI pairs at a 1/sec rate The thalam~c test stimulus ($2) is dehvered after the second SI-SI pair for a fixed t value The third and fourth S1-SI pmrs occur alone w~thout any test stimulus being delivered This procedure is then repeated for a different t value but for the same X value N o w let us return to the problem of determining a measure of machine output. A typical evoked response obtained from a test stimulus delivered for a t value of 85 msec is shown in Fig 1C1 The response is i n i t i a l l y s u r f a c e p o s i t i v e and resembles a damped oscillation In previous experiments 7,a we have used an average value, obtained by taking the area enclosed by the curve (Fig 1C, shaded area) over a 20 msec Interval and divided by the interval chosen, as an index o f machine output (Ya) An alternative measure of machine output would be to measure the peak amplitude of the Imtlal p o s i t i v e response (Yp) Fig 1C1 w a s obtained from the same case as A
B
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~
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,
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,
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i
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= 140
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Fig 2 Nonsequentlal test showing the change m machine output (Y) as a function of the pulse pair interval (t) N o sensory input used Each data point represents the mean ± S E M of 7 measurements A hnear approximation of the data has been assumed over a restricted range of t values (70-130 msec) The sohd hne was obtained by least squares analysis, with the slope of the line defined as the central rate sensmvlty (R) The dashed hnes Indicate the nonhnear regions Case N o 303 A, The peak measure for calculating machine output (Yp) has been used The product-moment correlation coefficient is 0 969 B, Same data as plotted in A with the area based measure used for calculating machine output (Y~) The product-moment correlation coefficient is 0 982
Bram Research, 38 (1972) 35-47
THALAMOCORTICALSYSTEM
39
Fig 1C2 and for the same t value (85 msec) Although the peak amphtude of the mmal positive response is Identical for both cases, the area enclosed by the curve has more than doubled m waveform 2 over 1 Waveform 2 (Fig 1C) was obtained after the contralateral brachlum conjunctwum (BC) was destroyed by electrocoagulatlon For the experiments illustrated in th~s paper, we wdl demonstrate that using the measure of initial peak (Yp), we obtained the same results as using the area definition (Ya) However, in any experiment where BC is opened or cerebellar influences are being studied, differences wdl become apparent between the two measures Machine output (Y) plotted as a function of the pulse pair Interval (t) is shown m Fig 2 (case No 303) In Fig 2A the peak measure (Yp) is used whereas m Fig 2B the same data are plotted using the area measure (Ya) Each data point represents the mean 4- S E M of 7 values Note that for t values between 70 msec and 130 msec the input-output relationship is approximately hnear, with the sohd hne (Fig 2) obtained by the method of least squares The product-moment correlation coefficient is 0 982 for Fig 2B using the area measure and slightly less (0 969) in Fig 2A using the peak measure The dashed lines illustrate the range of t values where the system becomes nonhnear A description of the response profile over an extended range of t values (50-250 msec) has been previously reported7, s In the hnear region between t = 70 and t : 130 msec the system can be approximated by the relation Y = R t q- K (in #V) relating the pulse pmr interval (t) m msec to the machine output (Y) in m~crovolts The slope of the hne we have termed central rate sensitivity (R), with the subscripted parameter Ra implying the area method for machine output ~s being used and Rp implying that the peak measure Is being used In the following illustrations we will show that the system parameter R can be varwd by peripheral signals This point is summarized m the diagram of Fig 1B where a change m machine output (AY) is related to a change m the pulse pair interval (At) by the system parameter R, with R being controlled by sensory input
Sensory control In order to demonstrate sensory control of the system parameter R, we conduct an S P - D P nonsequentlal test for a fixed X value We assume that a hnear approxamatlon is adequate over a range o f 7 equally spaced (10 msec) t values from 70 to 130 msec By using least squares analysis, we can then obtain an R value for a specific X Fig 3 illustrates central rate sensitivity (R) plotted as a function o f the peripheralcentral time difference (X) for case No 292, with Fig 3A showing R obtained by using the peak measure for machine output and with Fig 3B derived from the same data using the area measure. Both Fig 3A and B demonstrate that minimum R occurs at X = 0 and also that a second reduction in R occurs at X = + 7 5 msec The peripheral signal for this case (No 292) was a cutaneous electrical stimulus dehvered to the contralateral forepaw
Brain Research,38 (1972) 35~.7
40
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JOHNSON
AND G
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HANNA
41
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9~ •
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Fig 3 The relatton between central rate sensmvlty (R) and the peripheral-central time difference (X) when a random sequence of X values has been employed Note that minimum R occurs at X = 0 The product-moment correlation coefficient is m&cated for each R value The peripheral signal was originated by a cutaneous electrical snmulus dehvered to the contralateral forepaw The normal value obtained w~thout peripheral st~mulatlon is indicated by the arrow on the vertical axis The cortical recording site is indicated just anterior to and at the lateral end of the crucmte sulcus Case No 292 A, The peak measure for machine output (Yp) has been used to calculate Rp B, The area based measure for machine output (Ya) has been used to calculate Ra from the same data as used m A Note that the response profile is slmdar to that shown m A
W e have previously indicated that the sequence o f dehvery o f X values can also lnfluence the R parameter s For this reason the data o f Fig 3 were collected using a sequence w h i c h was determined by r a n d o m draw (X ---- - - 5 0 , no peripheral input, - - 1 0 0 , 6.100, 6.150, - - 1 5 0 , 6-50, 6-75, --25, 0, --75, 6-25) A single d e m o n -
stratlon is, of course, not sufficient to demonstrate that the minimum will rehably occur at R (X = 0), where R(X = 0) is read as 'the value of R at X = 0' A second test was conducted on this preparaUon ( N o 292) 30 mm later, following a different sequence, again determined by random draw (X = 6-25, 6" 100, --150, --100, --50, no peripheral input, --75, 0, 6-75, --25, 6-50, 6-150) The form of the response was virtually ldenUcal with the minimum R occurring at X = 0 and a second reduction at X = 6-75 msec (ref 8, Fig 6) The product-moment correlation coefficients are indicated adjacent to each data point in Fig 3 On the basis of the correlation coefficients there is no reason to state that the area measure of machine output is greatly superior to the peak measure In both cases the correlation coefficients drop as the slope (R value) of the approximating line is reduced This, of course, is to be expected Several examples o f this line rotation have been given previously a, where the R value changed from 2 5 / z V / m s e c to 0 3 5 / ~ V / m s e c and the correlation coefficient dropped from 0 98 to 0 62 (ref 8, Fig 4 A and B) It should be noted that each data point s h o w n in Fig 3
was obtained by fitting a line to 7 machine output values, equally spaced (10 msec) from t -- 70 to t = 130 msec, and is not an average of 7 tests as demonstrated in Fig 2 The small brain diagram m the center o f Fig 3 m & c a t e s the cortical recording
site for the data displayed Bram Research, 38 (1972) 35-47
41
THALAMOCORTICAL SYSTEM
A
B
! 5T r.._." >: / / \.,
i
o5
,/
-=
mo
."
."
50
:
/ I
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-
I
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I
mo +
X --ms@c
100
50
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-
'
i~0 +
X
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msec
Fig 4 The relationship between central rate sensitivity (R) and the peripheral--central time difference (X) when the peripheral signal has been originated by a binocular light flash A, The peak measure for machine output has been used Plot 1 was obtained by a symmetrical X sequence Plot 2 (dashed line) was obtained immediately after 1 utilizing a random sequence of X values Minimum R occurs at X = 0 in both cases The cortical recording site is represented by the open circle Case No 301 B, The area based measure for machine output (Y~) has been used to calculate Ra with a symmetrical X sequence being employed Again minimum R occurs at X = 0 The cortical recording site is represented by the filled circle Case No 300
Consider now the case illustrated in Fig 4 where visual signals (binocular light flash) were used to control R values In Fig 4A (case No 301) the peak measure for machine output has been used Fig 4A1 was obtained by using a symmetrical sequence of X values (X ---- dz 25, + 50, 0, --50, ± 100) In Fig 4A2 a second test was conducted immediately following the first using a r a n d o m sequence of X values (X ---- + 2 5 , --75, 0, --25, + 7 5 , + 5 0 , +100, --100, - - 5 0 ) With the exception of the values for R (X ---- + 2 5 ) both results take the same form with a minimum at R (X ----0) Note that both the symmetrical and random sequence started with X ---- + 2 5 msec. The area measure for machine output (Ya) has been used in Fig 4B, case N o 300, with visual input and a symmetrical presentation ( ± 2 5 , + 5 0 , 0, --50, ± 7 5 , -t-100) Minimum R again occurs at X ---- 0 with a second reduction in the X = + 5 0 to X = + 7 5 msec range The brain diagram in the center of Fig 4 indicates the cortical recording site with case N o 301, represented by the open circle, being slightly anterior to case No 300 (filled circle) Let us turn now to the situation when auditory signals (bilateral clicks, see Methods) are used (Fig 5, case No 302) In Fig 5A the peak measure for machine output has been used, with X values presented in symmetrical fashion ( ± 2 5 , + 5 0 , 0, --50, -4-100, :El50) Note that our 'tuning curve' is not as sharp as in Fig 3 with R (X = 0) and R (X = - - 5 0 ) both reduced Fig 5Ba shows the same data as in A but derived from the area measure for machine output Again, curve 1, Fig 5B shows the same broad minimum as in Fig 5A Curve 2, Fig 5B, was derived from the area measure and conducted immediately after curve 1 but in the reverse sequence (X ---= ZF 150, T 100, --50, 0, + 5 0 ) Note in Fig 5B curve 1, the sequence about zero was X -----+50-+X = 0-+X = --50, whereas in curve 2 the reverse sequence was used Brain Research, 38 (1972) 35-47
42
R N JOHNSON AND G R HANNA
A
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/"
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Fig 5 The relationship between central rate sensitivity (R) and the peripheral-central time difference (X) when the peripheral signal has been originated by a bilateral click The cortical recording site is represented by the filled circle Case No 302 A, The peak measure for machine output has been used with X values presented m symmetrical sequence Note the broad minimum extending from X = 0 lo X = - - 5 0 msec The arrows indicate the X sequence about zero (X = + 50 -~ X = 0 -7 X = --50) B, The area measure for machine output has been used to calculate Ra (plot 1) from the same dala as used m A Plot 2 (dashed line) was obtained immediately after 1, using a reverse sequence of X values The arrows indicate the X sequence about zero for each plot Note the X sequence sensitw ty of the R (X = 0) value
A
E
61.
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i
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100
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Fig 6 The relationship between central rate sensitivity (R) and the peripheral-central time difference (X) when the peripheral signal has been originated by an electrical stimulus delivered to the central footpad of the contralateral forepaw The peak measure for machine output has been used to calculate Rp The cortical recording site is represented by the filled circle Case No 304 A, Plot 1 was obtained by starting from the left (X = --150) and moving to the right (X = +150) Plot 2 was then obtained by starting from the right (X = + 150) and moving to the left (X = --150) Note the hysteresis effect m the victmty of X = 0 B, The procedure listed m A above was repeated Again note the hysteresis effect m the VlClmty of X = 0
Bram Research, 38 (1972) 35--47
THALAMOCORTICAL SYSTEM
43
(X = - - 5 0 - + X = 0-+X = 4 5 0 ) T h e greatest difference between curve 1 a n d 2 occurs at X = 0 W e c a n see t h a t the X sequence a p p e a r s to influence o u r results, p a r t i c u l a r l y at X = 0, the very p o i n t we c l a i m e d in F i g s 3 a n d 4 to p r o d u c e m i n i m u m R values. O f course, in n o n e o f the p r e v i o u s figures have we illustrated a s y m m e t r i c a l sequence which started w~th X = - - 1 5 0 msec It is i m p o r t a n t to note in F i g 5B t h a t in the vxcinity o f X -----0, f o r curve 2, we are a p p r o a c h i n g f r o m the right--1 e , X = + 100 a n d t h e n - - 5 0 ~ 0 - + + 5 0 - - - a n d m curve 1 we a p p r o a c h f r o m the l e f t - - t e , X = - - 2 5 a n d then 4 5 0 - + 0 > 50 T h e b r a i n d i a g r a m in the center o f F i g 5 indicates the cortical r e c o r d i n g site which, for this case ( N o 302), was medial to all p r e v i o u s examples A s y m m e t r i c a l sequence ~s n o t the best w a y to c o n s i d e r d i r e c t i o n sensltIwty as we are c o n t i n u a l l y a l t e r n a t i n g in a p p r o a c h d i r e c t i o n (sign o f X) F i g 6 illustrates 4 tests c o n d u c t e d o n a single a n i m a l ( N o 304) with two tests (solid lines) starting f r o m the left ( X = - - 1 5 0 ) a n d m o v i n g t o w a r d the right (X = + 150) a n d two tests ( d a s h e d lines) starting f r o m the right (X = + 150) a n d m o v i n g to the left (X = - - 1 5 0 ) T h e p e r i p h e r a l signal f o r this case ( N o 304) was delivered w a an electrical stimulus to the central f o o t p a d o f the c o n t r a l a t e r a l f o r e p a w T h e p e a k m e a s u r e for m a c h i n e o u t p u t was used In F i g 6 to calculate central rate s e n s m w t y (Rp) C u r v e 1, F i g 6 A was o b t a i n e d first, then curve 2, F i g 6 A The d a t a for curve 1, F i g 6B were then o b t a i n e d , f o l l o w e d b y curve 2, F i g 6B It t a k e s a p p r o x i m a t e l y 17 min to collect sufficient d a t a to calculate 11 R values (1 5 m m / R value), hence the d a t a d i s p l a y e d in F i g 6 represent 1 h o f testing N o t e in F i g 6A1, as we a p p r o a c h f r o m the left the R value d r o p s at X = - - 2 5 msec a n d r e m a i n s a t t e n u a t e d at X = 0 a n d then m o v e s b a c k to a h~gher value again at X = 4 2 5 msec W h e n we a p p r o a c h f r o m the right, R values r e m a i n high t h r o u g h the X = 0 p o i n t a n d t h e n d r o p at X = - - 2 5 msec This p r o d u c e s a hysterems
%, E
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1,50 " --
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160"
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Fig 7 The rel&t]onshlpbetween central rate sensmvlty (R) and the peripheral-central time difference (X) as obtained by averaging Each data point represents the mean :E S E M of 4 values, each of which were mdwldually plotted m Fig 6 Note that minimum R occurs at X = --25 msec However, the standard error of the mean is nearly twice as large at X = 0 than for any other X value since R (X = 0) is influenced by the dlrectmn of approach to X = 0 (Fig 6) Bram Research, 38 (1972) 35-47
44
R N JOHNSON AND G R HANNA
effect in the vicinity of X -- 0 This phenomenon is also demonstrated in Fig 6B, with the hysteresis effect m the WClmty of X =- 0 easier to observe since the R values outside the ± 5 0 msec range have not drifted apart as in Fig 6A The mean ~_- S E M (n = 4) of each R value from the 4 tests shown in Fig 6 is plotted in Fig 7 Note that the standard error of the mean is nearly twice as large at the X -- 0 point than for any other X value It is clear from Figs 5B and 6 that the prior sequence of X values determines whether R (X 0) assumes a high or low numerical value We believe the V L - M C system can be considered, in part, as a direction sensitive null detector with the peripheral-central time difference (X) being the input variable to which the neuronal machine responds For the case shown in Fig 6 the minimum or null point occurs at X = - - 2 5 msec when we approach from the right and is somewhat broader, covering the range from X = --25 to X =- 0, when we approach from the left The brain diagram in Fig 6 (case No 304) indicates that the cortical recording site w a s j u s t anterior to the lateral end of the cruclate sulcus DISCUSSION
Our general approach has been to consider the central input-output relationship, characterized by the parameter R, to be a reflection o f the state of the V L - M C system We have taken the viewpoint that it is the peripheral signal, impinging on the central processor, that brings about a change in the state of the system We have chosen to obtain R for a fixed peripheral-central time difference (X) and then illustrate R changes as a function of X It is important to stress that we have considered only the information contained in the time difference between the peripheral and the central stimulus In this respect, the V L - M C system does not appear to differentiate between sensory modahtles and will respond to the peripheral-central time difference irrespective of the source and site of Initiation of the peripheral signal The results one obtains from experiments of this kind are, of course, determined by the variables selected as measures of Input and output and the experimental pretocol employed In this paper we have Illustrated two methods of measuring machine output One method measured peak response and the second was an area based measure taken over a 20 msec interval Both measures produce similar representations of machine performance As we pointed out in Fig 1C, such would not be the case where, by experimental design, we open the contralateral brachlum conjunctlvum, for then wide differences between the peak and area based measures would appear A major question to consider is what inherent capability, as a dynamic signal processor, does the cat thalamocortlcal motor system have As such, a single cortIcal response has little meaning, for we are looking for a change In cortical response which is related to a change m the input The parameter termed the central ra~e sensitivity (R) relates the change in machine output ( A y ) to a change in the input (pulse pair interval, At) The R value becomes a measure of the state of the system The R parameter follows from the assumption that the system is approximately linear for t values from 70 to 130 msec The R parameter, which we say reflects the state of the system, was found to be a function of the peripheral--central time difference (X) From the results
Bram Research, 38 (1972) 35-47
THALAMOCORTICAL SYSTEM
45
shown in Figs 3-7 we conclude that the V L - M C system can perform as a null detector or signal coincidence detector That is, as the peripheral and central stlmuh move toward correspondence the R parameter moves to a minimum value The null point occurs at X = - - 2 5 msec (peripheral signal leads central by 25 msec) for the case shown m Fig 6 with the value for R(X ----0) being either high or low depending on the previous sequence of X values dehvered The V L - M C system has the capability to perform as a null detector whose ultimate response profile is dependent on the sequence of X values employed Asanuma et al 1 have suggested that afferent inputs from restricted peripheral loci 'reflexly' induce muscle contraction through a loop including motorsensory cortex, and they cite as an example the wellknown 'tactile placing reaction' m the cat It has been further suggested by Asanuma et al 1 that cutaneous input may serve as feedback information during a pursuit movement Elements of both of these suggestions have been incorporated into our experimental design We have maintained the amplitude of the peripheral stimulus delivered to the contralateral forepaw at a level just sufficient to produce wrist movement The timing between the peripheral stimulus and the central stimulus then forms that quantity of information which we have termed the peripheral-central time difference (X) As discussed above, the dynamics of the central system, as characterized by the parameter R were shown to be a function of X We can understand that cutaneous input may well serve as feedback information during a complex pursuit movement However, more sophisticated test protocols must be devised, considering visual, auditory and somesthetlc inputs, in order to delineate the underlying central dynamics associated with complex movements We have previously shown that the V L - M C system forms a 'self-modifying' machine, l e , a machine whose cortical response is due to both incoming information and information i r o m its past history of use 7,8 This influence from the past IS again evident in the hysteresis phenomenon about X = 0, as demonstrated in Figs 5B, 6 and 7 We feel that any protocol devised to test the V L - M C system must always consider the state of the system as determined by its past history, in addition to Incoming information (input) as the determinants of the response (output) Our 'black box' methods of manipulating Inputs and measuring outputs are designed to demonstrate the dynamic performance capabilities of the V L - M C system and not to extract information about the internal 'parts' (neurons, etc ) within the box Creutzfeldt et al 5 show an average IPSP of a cortical cell following 1/sec ventrolateral stimulation Inspection of their data (ref 5, Fig 10C) shows that the IPSP plotted as a function of time is approximately linear in the range from 70 to 130 msec after the stimulus It seems reasonable to assume that the approximate hnearity of the IPSP versus time plot is reflected in the linear relation that we have shown in Fig 2 We do not know at this time whether the slope of the IPSP versus time curve can be shown to be a function of the peripheral-central time difference (X) There is little doubt that cat pericruclate corCex receives a wide range of sensory inputs1,2,4,11,12,14-10 with m a n y neurons, primarily in precruclate tissue, being polysensory 11 Quant~tatlve functional relationships between variables describing the thalamocort~cal m o t o r system at the neuronal level remain to be developed It is our belief that an underBram Research, 38 (1972) 35-47
46
R N JOHNSON AND G R HANNA
standing of the dynamic relationships of large neuronal aggregates will prowde gmdehnes for further quantltatwe studtes at the neuronal level Differences at the neuronal level between precrucmte and postcrucmte cortex have recently been summarized by Nyqmst and Towe 11 All of the data reported m our study were obtained from a cortical recording site either lmmedmtely anterior to or at the lateral end of the crucmte sulcus In 10~o of the cases studied we have successfully recorded from postcrucmte tissue It is possible to control, at least by electrical stimulation of the contralateral forepaw, the R parameter derived from measurements taken from postcruclate t~ssue The response profile ~s similar to that reported here, but the null point is shifted to the left m the range of X ------ - 5 0 to X = --75 msec (ref 8, Fig 5B) SUMMARY
A hnear approximation of the input-output relatmnshlp between ventrolateral (VL) nucleus and sensorlmotor cortex (MC) in the cat has been employed The slope of the transfer function has been termed the central rate sensltwlty (R) It has been shown that the system parameter R can be controlled by the time interval between a central thalam~c stimulus and a peripheral stimulus, e~ther auditory, visual or somesthetlc The response profile of the system, plotting central rate sensmwty (R) as a function of the peripheral-central time difference (X) indicates that the V L - M C system can perform as a null detector, w~th minimum R values occurring m the vicinity of peripheral-central signal correspondence The system shows considerable hysteresis m the regmn of X = 0 with the value for R(X = 0) determmed by the dlrecUon of approach toward X -~ 0, where the term direction lmphes a lead or lag relationship between the peripheral and central stimulus ACKNOWLEDGEMENTS This research was supported m part by grants from U S Pubhc Health Service (No F3-Gm-35,680 and NB 05120) and Social and Rehabdltatlon Service, Department of Health, Education and Welfare (No R D 1870-M) We are mdebtexi to Mrs Sharon Trader for her technical assistance
REFERENCES 1
ASANUMA, H , STONEY, S
D, JR, ANDAaZUG,C, Relationship between afferent input and motor outflow m cat motorsensory cortex, J Neurophyslol, 31 (1968) 670-681 2 BROOKS,V B, Information processing m the motorsensory cortex In K N LEIBOVIC(Ed), Information Processing m the Nervous System, Spnnger, New York, 1969, pp 231-243 3 BUSER,P, Subcortlcal controls of pyramidal acUwty In D P PURPURAANDM D YAHR(Eds), The Thalamus, Columbia Umv Press, New York, 1966, pp 323-344 4 BusEs, P, AND IMB~RT,M, Sensory projectmns to the motor cortex m cats A mlcroelectrode study In W A ROSl/NSLITH(Ed), Sensory Commumcatton, Wdey, New York, 1961, pp 607-626 5 CREUTZFELDT, O D , LUX. H D , AND WATANABE, S , Electrophystology of cortical nerve cells. Brain Research, 38 (1972) 35-47
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6 7
8 9 10 11 12 13 14
15
16
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In D P PURPURA AND M D YAHR (Eds), The Thalamus, Columbia U m v Press, New York, 1966, pp 209-230 HANNA, G R , AND JOHNSON, R N , A rap~d and simple method for the fabrication of arrays of recording electrodes, Electroenceph din Neurophystol, 25 (1968) 284-286 JOHNSON, R N , AND HANNA, G R , The thalamocortlcal system as a neuronal machine the interaction of ventrolateral nucleus with sensonmotor cortex m the cat, Brain Research, 18 (1970) 219-239 JOHNSON, R N , ANt) HANNA, G R , An elementary description of thalamocort~cal system dynamics m the cat, Brain Research, 31 (1971) 119-137 MOUNTCASTLE, V B , AND HENNEMAN, E , Pattern of tactile representation in thalamus of cat, J Neurophyslol, 12 (1949) 85-100 MOUNTCASTLE, V B , POGGIO, G F , ANt) W~RNER, G , The relation of thalamlc cell response to peripheral stlmuh varied over an intensive continuum, J Neurophyslol, 26 (1963) 807-834 NYQUIST, J K , AND TOWE, A L , Neuronal activity evoked m cat precruclate cerebral cortex by cutaneous stimulation, Exp Neurol, 29 (1970) 494-512 OSCARSSON, O , AND ROS~N, I , Short-latency projections to the cat's cerebral cortex from skin and muscle afferents m the contralateral forelimb, J Physwl (Lond), 182 (1966) 164-184 Poc~3IO, G F , ANt) MOUNTCASTLE, V B , The functional properties of ventrobasal thalamlc neurons studied m unanesthetized monkeys, J Neurophystol, 26 (1963) 775-806 TOWE, A L , PATTON, H D , ANt) KENNEDY, T T , Response properties of neurons m the pen. crucmte cortex of the cat following electrical shmulation of the appendages, Exp Neurol, 10 (1964) 325-344 WELT, C , ASCHOFF, J C , KAMEDA, K , AND BROOKS, V B , Intracortlcal organization of cat's motorsensory neurons In M D YAHR, AND D P PURPURA (Eds), NeurophyswlogwalBasts of Normal and Abnormal Motor Actlvmes, Raven Press, Hewlett, N Y , 1967, pp 255-288. WHITEHORN, D , AND TOWE, A L , Postsynapt~c potentml patterns evoked upon cells m sensonmotor cortex of cat by stimulation at the periphery, Exp Neurol, 22 (1968) 222-242
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