Frequency-dependent response of SI RA-class neurons to ...

Correspondence: B. L. Whitsel, Ph.D., 155 Medical Research, CB#7545, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA. Tel.: + 1–919–966–1291; 966–9055; Fax: + 1–919–966–6927; E-mail: [email protected]

Frequency-dependent response of SI RA-class neurons to vibrotactilestimulation of the receptive field

B. L. WHITSEL1,2, E. F. KELLY3, M. XU2,3, M. TOMMERDAHL2 and M. QUIBRERA1,4

1Department of Cell and Molecular Physiology; 2Department of Biomedical Engineering, UNC School of Medicine;3Department of Diagnostic Sciences, UNC School of Dentistry; 4Department of Statistics, University of North Carolina,Chapel Hill, NC 27599, USA

AbstractThree types of experiment were carried out on anesthetized monkeys and cats. In the first, spike discharge activity of rapidly adapting (RA)SI neurons was recorded extracellularly during the application of different frequencies of vibrotactile stimulation to the receptive field (RF).The second used the same stimulus conditions to study the response of RA-I (RA) cutaneous mechanoreceptive afferents. The third usedoptical intrinsic signal (OIS) imaging and extracellular neurophysiological recording methods together, in the same sessions, to evaluate therelationship between the SI optical and RA neuron spike train responses to low- vs high-frequency stimulation of the same skin site. RAafferent entrainment was high at all frequencies of stimulation. In contrast, SI RA neuron entrainment was much lower on average, and wasstrongly frequency-dependent, declining in near-linear fashion from 6 to 200 Hz. Even at 200 Hz, however, unambiguous frequency-following responses were present in the spike train activity of some SI RA neurons. These entrainment results support the “periodicityhypothesis” of Mountcastle et al. (J Neurophysiol 32: 452–484, 1969) that the capacity to discriminate stimulus frequency over the range5–50 Hz is attributable to the ability of SI RA pyramidal neurons to discharge action potentials in consistent temporal relationship tostimulus motion, and raise the possibility that perceptual frequency discriminative capacity at frequencies between 50 and 200 Hz might beaccounted for in the same way. An increase in vibrotactile stimulus frequency within the range 6–200 Hz consistently resulted in an increasein RA afferent mean spike firing rate (MFR). SI RA neuron MFR also increased as frequency increased between 6 and 50 Hz, but declinedas stimulus frequency was increased over the range 50–200 Hz. At stimulus frequencies > 100 Hz, and at positions in the RF other thanthe receptive field center (RFcenter ), SI RA neuron MFR declined sharply within 0.5–2 s of stimulus onset and rebounded transiently uponstimulus termination. In contrast, when the stimulus was applied to the RFcente r , MFR increased with increasing frequency and tended toremain well maintained throughout the period of high-frequency stimulation. The evidence obtained in “combined” OIS imaging andextracellular microelectrode recording experiments suggests that SI RA neurons with an RFcen te r that corresponds to the stimulated skin siteoccupy small foci within the much larger SI region activated by same-site cutaneous flutter stimulation, while for the RA neurons locatedelsewhere in the large SI region activated by a flutter stimulus, the stimulus site and RFcen te r are different.

Key words: somatosensory, cerebral cortex, vibration, flutter, spike discharge entrainment, periodicity coding, frequency discrimination

Introduction

Optical intrinsic signal (OIS) imaging studies (Tom-merdahl & Whitsel, 1996; Tommerdahl et al., 1998,1999a, b) have demonstrated that SI cortex respondsdifferentially to same-site cutaneous flutter (25 Hz)vs vibration (200 Hz). In cats and monkeys 25 Hzstimulation reliably produced, as expected, anincrease in optical absorbance in the topographicallyappropriate region of SI. An increase in the opticalabsorbance of sensory cortex is known to reflectincreased concentration of K + in the extracellularspace, glial swelling, and perhaps other sequelae oflocal neuronal activity (Grinvald et al., 1991, 1994,1999; Holthoff and Witte, 1996; Kohn et al., 2000).The time course of the absorbance increase evokedin SI by 25 Hz flutter stimulation was generallyconsistent with published descriptions (Mountcastleet al., 1969, 1990) of the spike discharge response ofSI RA neurons to such stimulation—it began within

milliseconds of stimulus onset, was relatively wellmaintained throughout the period of stimulation,and decayed to prestimulus levels shortly afterstimulus termination.

A very different sequence of optical changesoccurred in SI when the skin was stimulated at200 Hz (Tommerdahl et al., 1999a, b). During theinitial 1–3 s of 200 Hz stimulation there was anincrease in SI absorbance indistinguishable in magni-tude and spatial extent from the absorbance changesdetected at the same time after onset of 25 Hzstimulation of the same skin site. With continuing200 Hz stimulation, however, absorbance decreasedin most of the SI region that had responded to 25 Hzstimulation, except at one or, more frequently,several relatively small loci where an increase inabsorbance persisted until stimulus termination.

Two further observations indicated that the promi-nent changes in both the spatial profile and magni-tude of the SI OIS that occurred during an exposure

ISSN 0899–0220 (print)/ISSN 1369–1651 (on line)/01/040263–23 © 2001 Taylor & Francis LtdDOI: 10.1080/0142159012008965 9

Somatosensory & Motor Research 2001; 18(4): 263–285

to continuous high-frequency skin stimulation wereattributable at least in part to active inhibition, ratherthan just an activity-dependent decrease in mecha-noreceptor afferent responsivity (Leung, 1994;Leung et al., 1994). First, within several secondsafter the onset of 200 Hz vibration, absorbance in thetopographically appropriate regions of SI not onlydeclined sharply from the values reached shortlyafter stimulus onset, but often fell to levels belowthose observed prior to stimulus onset, even asabsorbance continued to increase in the topographi-cally appropriate sector of the neighboring SII(Tommerdahl et al., 1999a, b). Second, the normallyrobust and well-maintained absorbance increaseevoked in SI by a 2–5 s exposure to 25 Hz flutterunderwent a rapid and substantial reduction in arealextent and intensity when a 200 Hz component wassuperimposed on the much larger amplitude flutterstimulus (Tommerdahl et al., 1999b).

These OIS imaging results were tentatively inter-preted to indicate (1) that the spike discharge activityof most RA-type SI pyramidal neurons increases onlytransiently in response to the vigorous activity asuprathreshold high-frequency stimulus evokes inthe central projections of RA-I (RA) afferents, and(2) that within 1–3 s after stimulus onset the effect onthese same SI RA neurons of continuing high-frequency afferent drive becomes predominantlyinhibitory (Tommerdahl et al., 1999a, b). Thisinterpretation is consistent with the strong positivecorrelation consistently reported between opticalabsorbance and sensory cortical neuron spike dis-charge activity (Grinvald, 1985; Grinvald et al.,1991, 1994, 1999, 2001; Tommerdahl and Whitsel,1996; Tommerdahl et al., 1999a, b), the scarcity of SIpyramidal neurons that receive their principal inputfrom RA-II (Pacinian, PC) afferents (Mountcastle etal., 1969, 1990), and the exquisite responsivity of SIGABAergic intrinsic neurons to high-frequencyinput drive (McCormick et al., 1985). However, ithas not yet been directly verified by a detailedanalysis of the behavior of RA-type SI neuronsduring high-frequency skin stimulation.

The present paper fills this gap by reporting resultsof analyses of the spike discharge activity of RA-classSI pyramidal neurons in response to stimulation ofthe RF at frequencies of vibrotactile stimulationbetween 6 and 200 Hz. The main results wereobtained by systematically applying analytical tech-niques which enable measurement of entrainmentquantitatively, and independently of responsivity,across a range of vibrotactile stimulus amplitudesrepresentative of those encountered during everydaylife (Whitsel et al., 2000). To address the possibilitythat frequency dependencies in the responses of SIRA neurons might merely reflect the effects ofstimulus frequency at the sensory periphery, we alsoevaluated the effects of same-site flutter vs vibratorystimuli on the spike discharge activity of RAafferents.

MethodsSubjects/general procedures

All procedures are consistent with USPHS and NIH policies andguidelines on animal care and welfare in biomedical research, andwere reviewed and approved by an institutional committee prior toinitiation of the experiments.

Afferent recording experiments Cutaneous mechanoreceptor affer-ent spike discharge activity was recorded in three monkeys(Macaca nemistrina) and in two cats (Felis domestica). A surgicallevel of general anesthesia was achieved with pentobarbital(25–30 mg/kg, i.v.). Skeletal neuromuscular transmission wasblocked by Norcuron (vecuronium bromide 0.25–0.5 mg/kg, i.v.).Positive pressure respiration was provided via a tracheal tube.End-tidal CO2 was maintained between 3.5 and 5.0%. Glucose(5%) and 0.9% saline were administered intermittently tomaintain normal metabolism, hydration, and electrolyte balance.Supplemental neuromuscular blocking drug and anesthetic wereadministered i.v. on regular schedules (Norcuron 0.025–0.05 mg/kg/h; pentobarbital 2–5 mg/kg/h).

The median (forelimb) or tibial (hindlimb) nerve was exposed,freed from surrounding tissues, covered with mineral oil, andtransected central to the recording site. Filaments were dissectedusing fine forceps, and placed one-at-a-time onto a Ag–AgClrecording electrode connected to conventional neurophysiologicalmonitoring instrumentation. Filaments from which vigorousmulti-unit spike discharge activity could be evoked by hand-heldmechanical stimulation (using fine brushes and/or probes) ofeither the volar surface of the hand or foot (monkeys), or the padsof the distal forepaw (cats) were subdivided until the actionpotentials of individual afferents were evident. Afferents wereclassified as rapidly adapting (RA; more precisely, RA-I; Vallbo etal., 1984) if spike discharge activity (1) could be evoked byapplication of gentle mechanical stimuli to a localized skin site, (2)was absent or rare in the absence of such stimulation, and (3)occurred only transiently in response to maintained mechanicalcontact with the RF.

Spike discharge activity of RA afferents was recorded from 26different fibers/filaments. Eight recordings of monkey RA spikedischarge activity met the standard criteria (consistency of actionpotential amplitude and waveform) for activity deriving from asingle fiber (SUR), while for four additional recordings the activitywas judged to derive from two or three RA afferents (MURs) eachof which had an RF that included the skin site contacted by thestimulator probe. Fourteen RA afferents were studied in cats, allmeeting SUR criteria. Euthanasia was accomplished by i.v.administration of pentobarbital (50 mg/kg).

Cortical recording experiments Extracellular microelectrode record-ings of SI neuron spike discharge activity were obtained in fivemonkeys (three macaques—Macaca nemistrina and two squirrelmonkeys—Saimiri sciureus) and in five cats (Felis domestica). Theexperiments on macaques yielded recordings from both corticalneurons and mechanoreceptive afferents, with the cortical record-ings always carried out first.

General anesthesia was induced by supplying 4% halothane in a50/50 mixture of oxygen and nitrous oxide to a light- and air-tightenclosure housing the subject. The trachea was intubated and thetracheal tube connected to an anesthesia machine (ForregerCompac-75). The anesthetic gas mix was adjusted (typically1.5–3.0% halothane in 50/50 N2O/oxygen) to maintain a stablelevel of surgical anesthesia. Methylprednisolone sodium succinate(20 mg/kg) and gentamicin sulfate (2.5 mg/kg) were injectedintramuscularly to lessen the probability of halothane-inducedcerebral edema and prevent bacterial septicemia, respectively. Avalved catheter in a superficial hindlimb vein enabled administra-tion of drugs, glucose (5%), and electrolytes (0.9% saline).

A 1.5 cm opening was trephined in the skull overlying SI cortex.A recording chamber (25 mm i.d.) was positioned over theopening and cemented to the skull with dental acrylic. Woundmargins were infiltrated with local anesthetic, closed with suturesand bandaged, and the dura overlying SI incised and removed.After completion of surgical procedures subjects were immobi-lized with i.v. Norcuron (loading dose 0.25–0.5 mg/kg; main-tenance dose 0.025–0.05 mg/kg/h). From this point on, the 50/50mix of N2O and oxygen was provided via a positive pressureventilator and the concentration of halothane adjusted (typicallybetween 0.5 and 1.0%) to maintain heart rate, blood pressure, and

264 B. L. Whitsel et al.

the EEG at values consistent with general anesthesia. Rate anddepth of ventilation were modified to maintain end-tidal CO2

between 3.0 and 4.5%.After obtaining a high-resolution photograph of the exposed

cortical surface the recording chamber was filled with artificialcerebrospinal fluid and closed with a clear glass plate containingan “o”-ring. The “o”-ring permitted a microelectrode to beadvanced while maintaining hydraulically sealed “closed-cham-ber” conditions, thus minimizing cortical and vascular movementsassociated with the cardiac and respiratory cycles. The glass plateenabled (via an operation macroscope) determination of theprecise site and micrometer position at which the microelectrodemade initial contact with SI cortex. Extracellular recordings ofneuronal spike discharge activity were obtained using glass-insulated tungsten wires (impedance 300–500 k V at 10 kHz). Atthe maximal depth of a penetration, and also at sites whererecordings of particular interest had been obtained, a microlesionwas created by passing 1–10 m A of d.c. current through themicroelectrode.

Euthanasia was by i.v. administration of pentobarbital (50 mg/kg) followed by intracardial perfusion with 0.9% saline and 10%formalin. The region of SI studied was removed and seriallysectioned at 30 m m; monkey SI was sectioned in the sagittal plane,cat SI in the coronal plane. Sections were mounted on glass slides,Nissl-stained, coverslipped, and inspected microscopically. Areas3a, 3b, 1 and 2 were distinguished on the basis of establishedcytoarchitectonic criteria (monkey—Powell and Mountcastle,1959; Jones and Porter, 1980; Sur et al., 1982; cat—Hassler andMuhs-Clement, 1964; McKenna et al., 1981). Microelectrodetracks were plotted using a microscope with a drawing tubeattachment. The sites at which recordings were made along eachtrack were reconstructed using the three types of micrometerreadings recorded for each microelectrode penetration: (1) posi-tion where the microelectrode made contact with the pial surface;(2) locus at which spike discharge activity was recorded; and (3)depth at which each microlesion was placed.

In four experiments (two squirrel monkeys, two cats) the OISresponses evoked in SI by 25 Hz flutter and by 200 Hz vibrationwere recorded prior to microelectrode recording, using an imagingsystem employed in previous studies (for methodological detailssee Tommerdahl et al., 1999a, b). The system consisted of acomputer-interfaced CCD camera, the light source, guide, andfilters required for near-infrared (833 nm) illumination of thecortical surface, a focusing device, and a recording chamber withan optical window. Near-infrared illumination was used because itminimizes the contributions to OIS images of the changes in bloodflow and flow/volume that normally accompany cortical neuronalactivation, and also because the intrinsic signal obtained at 833 nmexhibits substantially higher spatial and temporal resolution thanthe signals recorded at lower wavelengths.

Once OIS images of the SI response to 25 and 200 Hzstimulation of the same skin site had been obtained, the opticalrecording system was disassembled and replaced with the appara-tus for performing extracellular microelectrode recordings. Thegoal of the microelectrode recording component of each com-bined OIS imaging/neurophysiological recording experiment wasto characterize the spike train responses of SI RA neurons atknown locations within the optical response pattern producedunder the same stimulus conditions.

Vibrotactile stimulation

A mechanical stimulator (Chubbuck, 1966) was used to deliversinusoidal vertical skin displacement stimuli to a skin locus fromwhich hand-held gentle mechanical stimuli evoked vigorous SIneuron or RA afferent spike discharge activity. The stimulatormade contact with the skin via the flat end of a plastic cylindricalprobe (2 or 5 mm in diameter) threaded to the stimulator shaft.Sinusoidal probe motion began at phase zero (at 1.0 mm skinindentation), and initially advanced further into the skin. Sincepeak-to-peak amplitude of the sinusoid never was greater than0.6 mm, the probe remained in contact with the skin duringstimulation. In most studies the probe continued to indent theskin during the interval between successive stimuli (“trials”). Inseveral experiments the stimuli were superimposed on an inter-mittent “pedestal”—i.e., the probe was maintained in a positionabove the skin surface prior to stimulation, advanced rapidly(10 ms) to produce 1.0 mm of skin indentation at 100–200 msbefore the onset of sinusoidal stimulation, and retracted to the off-the-skin rest position 100–200 ms after stimulus termination.

Similar stimulus conditions and protocols were used to studyafferents and cortical neurons. Each neuron and afferent wasstudied with at least one frequency selected from the range offrequencies humans experience as flutter (5–50 Hz), and anotherfrom the range humans experience as vibration (60–200 Hz).Most afferents and neurons were studied using 5–7 frequencieswithin the range 6–200 Hz, presented in either fully randomizedor interleaved order.

Neural data collection/analysis

Spike discharge activity and an analog signal of stimulus positionwere digitized at 20 kHz. Software allowed post-experimentaldisplay and review of both neuroelectrical and stimulator events. Ahigh-resolution monitor was used to inspect the relationshipbetween spike firing and stimulator events, evaluate actionpotential waveforms, and discriminate (using voltage windows)spikes attributable to different units. For each recording 1–3 non-overlapping voltage windows were selected so that each containedaction potentials attributable either to a single unit or to a smallgrouping of units. An electronic file was generated for every run,containing the times of occurrence of the action potentials fallingwithin each voltage window, and the times of specific stimulatorevents (onset and termination of the pedestal, onset of eachindividual stimulus cycle, termination of each trial, etc.).

Two aspects of spike discharge activity are especially relevant tothe perception of vibrotactile stimuli, and these were measuredseparately. The first, responsivity , was measured by counting thenumber of spikes in a designated time period and then dividingthat count by the number of stimulus cycles. Incomplete stimuluscycles were ignored in this calculation. For SI RA neurons themeasure of responsivity was adjusted in two ways to correct for thesignificant amounts of spontaneous or background activity typi-cally present: the first method subtracted background mean firingrate (MFR) from the MFR during the stimulus period beforeconverting to spikes/cycle (adjusted and unadjusted MFRs werecorrelated, < 0.95). The second used background mean firing rateas a covariate in analysis of variance (ANOVA) of the unadjustedresponsivity. Corresponding results from these two approacheswere invariably highly similar. Responsivity was measured for twooverlapping time periods (0–0.5 and 0–2 s after stimulus onset),in order to detect and characterize, at least crudely, possible rapidchanges in unitary activity following stimulus onset. For someruns stimulus duration was 0.8 s, and for these responsivity wascomputed for the periods 0–0.5 and 0–0.8 s after stimulusonset.

Entrainment , the organization of spike discharge activity intoorderly temporal patterns coupled to the sinusoidal motion of thestimulus, was assessed using three measures which collectivelyenable entrainment to be measured quantitatively under a widevariety of stimulus conditions (Whitsel et al., 2000). All threemeasures take values between 0 and 1, with 1 indicating perfectentrainment. The first, r1 , derives from the theory of circularstatistics (Batschelet, 1981), and measures the tendency of spikesto cluster near a single modal or most-favored position in thestimulus cycle. This behavior corresponds to the classical view ofneuronal entrainment as developed by Talbot et al. (1968) for skinmechanoreceptive afferents. The second, r2 , extends the approachembodied by r1 to the specific and physiologically commonsituation in which spikes are generated approximately 180° apartin the stimulus cycle. This often occurs, for example, for Pacinian(PC or RA-II) afferents even at low amplitudes of sinusoidalstimulation, and for RA-I afferents exposed to moderate-to-largestimulus amplitudes (Johansson et al., 1982; Whitsel et al.,2000).

The third measure, rs , takes a more general approach based onspectral analysis of spike trains. Each record to be analyzedconsists initially of a sequence of events of unit amplitude (thespikes) occurring at precisely known but unequally spaced times.This record is first transformed into a series of samples spacedequally in time, using an algorithm which has been demonstrated(French and Holden, 1971a, b) to yield unbiased and alias-freeestimates of the power spectrum. This “resampling” is carried outat a rate ³ 10 times the stimulus frequency, in order to capture aminimum of five harmonics in the power spectrum. The trans-formed record, in turn, is centered, detrended, and converted tostandard scores (mean zero, variance one) in order to removevariation due to the overall response level. Its power spectrum thenis calculated using conventional FFT-based methods (Marple,1987). The resulting measure of entrainment, rs , reflects the

Vibrotactile frequency coding 265

proportion of the normalized signal amplitude appearing at thestimulus frequency and its integral harmonics. For full details, seeWhitsel et al. (2000), who demonstrated that rs approximates r1

for monopolar patterns of phase-locked spike discharge activity,approximates r2 for bipolar patterns, and yields high values formany additional, more complex patterns that neither r1 nor r2 caneffectively measure. In this paper we use the highest of the threemeasures calculated for a given record as the final, best measure ofthe degree of entrainment for that record—denoted “rb”. Table 3gives the number and proportion of SI RA neurons (total sample= 324) for which r1 , r2 , or rs yielded the highest measure ofentrainment.

The central aim was to investigate effects of stimulus fre-quency on unit responsivity and entrainment. To that end, foreach afferent or cortical neuron the data generated in trials inwhich the same frequency was applied were grouped to form asingle “run”, and measures of responsivity and entrainment werecalculated for that run as a whole. The entrainment measures r1

and r2 were calculated based on all available spikes, and rs wascalculated from the time average of the corresponding resampledtrial-by-trial records. The results of each run were entered into adatabase containing, in addition to the measures of neuroelec-trical activity, descriptors of the associated experimental condi-tions—for example, experiment and unit ID, and stimulusproperties such as frequency, amplitude, duration, and contactorsize. Both the spike discharge activity of individual SI RAneurons (“single-unit” recordings—SURs) and the activity ofsmall RA neuron groupings (consisting of 2–5 neurons; “multi-unit” recordings—MURs) were studied. In all, 21 RA singleneurons and 9 RA MURs were studied in monkeys; and 38 RAsingle neurons and 13 RA MURs in cats. Consideration of thepossibility that the measures of entrainment and responsivityobtained from a MUR might deviate from those obtained from aSUR led us to (1) label each digitized record of neuronal activity(file) in a way that identified it as a record of single- or multi-unit spike discharge activity, and (2) evaluate the two types ofdata (single unit vs MUR) separately.

Separate databases were constructed for the records of RAafferent and cortical neuron activity. The afferent databasecontained information derived from 103 runs carried out on the22 single RA afferents and 4 small groupings of RA afferents; thecortical neuron database summarized the results of 326 runscarried out on the 59 single SI RA neurons and 22 small SI RAneuron groupings. Table 1 summarizes the experimental condi-tions associated with both databases.

Quantitative treatment of the information in the databasesconsisted mainly of analyses of variance using the neuroelectricalresponse measures as dependent variables, and stimulus frequencyas the primary independent variable. Statistical analyses and plotswere generated using SYSTAT and MATLAB under Windows 98.

Results

Representative observations

The results shown in Figures 1–4 were obtainedfrom a single SI RA neuron and a single RA afferentrecorded in the same subject. Each unit was exposedto 15 repetitions of continuous (2 s duration),100 m m amplitude sinusoidal stimulation at fivedifferent frequencies (12, 25, 50 100, and 150 Hz;see figure legends for additional details). The rasterplots in Figure 1 show the time series of spikesrecorded during each stimulus, and also during theinitial 1 s of the 15 s interstimulus interval (ISI).

Substantial differences between the spike firingbehaviors of the SI RA neuron and the RA afferentare apparent. First, the neuron, but not the affer-


TA BL E 1. Experimental variables

Variables/levels RA afferents(N = 26)

No. of runs = 103

RA neurons(N = 81)

No. of runs = 326

Stimulus amplitudes ( m m, p-p)50 18 22

100 85 177200 – 65350 – 31600 – 31

Stimulus duration (s)0.8 – 342 25 1333 36 265 42 93

> 10 – 40

Contactor sizes (mm)2 14 915 89 235

Pedestal typeContinuous 103 183Interrupted 0 143

Discharge typeSUR 79 242MUR 24 84

SpeciesCat 36 169Monkey 67 157


FIG U RE 1. Spike trains recorded from an exemplary SI RA neuron (five raster plots on left) and RA afferent (right), both studied in the samesubject. Each raster plot shows the responses to 15 consecutive presentations of a given frequency of stimulation to the RFcente r. At allstimulus frequencies amplitude = 100 m m, duration = 2 s, ISI = 15 s. Probe diameter was 2 mm for the SI neuron, 5 mm for the afferent.Downward arrows indicate stimulus termination. The RF of the neuron (area 1, lamina III) included the proximal pad of digit 2 and theneighboring part of the medial interdigital pad on the foot. The RF of the afferent was confined to the distal pad of digit 2 of the foot.


FIG U RE 2. Circular histograms and rb values for the spike train data of Figure 1. Line lengths are scaled relative to the most frequentlyoccurring angular position.

ent, exhibited a level of spontaneous firing suffi-ciently high and variable to obscure the boundarybetween the stimulus and no-stimulus periods atevery stimulus frequency. Second, while the neu-ron’s mean spike firing rate (MFR), like the affer-ent’s, increased with increasing stimulus frequencywithin the range 10–50 Hz, the magnitude of theincrease was much smaller than that of the afferent.Third, although the afferent displayed a metro-nome-like capacity to follow the sinusoidal stimulusthat is visually obvious up to at least 50 Hz (it is lessapparent at the higher frequencies only because ofthe time scale of the raster plots in Fig. 1),entrainment of the neuron’s spike discharge activityis apparent only at the lowest frequency. Specifi-cally, at 12 Hz, but not at any of the higherfrequencies, the vibrotactile stimulus caused theneuron to discharge bursts of spikes at roughlyconsistent positions in the stimulus cycle. Fourth,the afferent showed a much stronger tendency, withincreasing stimulus frequency, for MFR to declineboth within and across trials.

The contrast between the entrainment behaviorsof the same RA afferent and SI RA neuron iscaptured more completely and quantitatively bycircular histogram analysis (Fig. 2; note that acircular histogram is in essence a cycle histogram, theends of which have been joined together). For the

afferent the pattern of action potential phase lockingto the sinusoidal stimulus is of the classic monopolar(r1 ) type, and it is apparent that the high degree ofentrainment visually evident in the spike raster plotsfor frequencies between 10 and 50 Hz was main-tained all the way to the highest frequency (150 Hz).By contrast, the circular histograms on the left revealthat the lesser entrainment exhibited by the SI RAneuron at 12 Hz degraded substantially and pro-gressively as stimulus frequency increased. At thetwo highest frequencies, in fact, the timing of spikefiring appears essentially unrelated to the stimuluscycle (i.e., rb < 0).

Further contrasts between the same SI RA neuronand RA afferent are made evident by Figure 3, whichfor both units plots responsivity and entrainment asfunctions of trial number (top four plots) andtemporal position within the stimulus period (bot-tom four plots). For this neuron, but not the afferent,responsivity decreased drastically with increasingfrequency, especially within the range 10–50 Hz. Inaddition, for the afferent entrainment was uniformlyhigh and stable both across and within trials at allstimulus frequencies, whereas for the SI neuronentrainment was not only frequency-dependent, butconsiderably more variable with some suggestion oftemporal trends most evident within the flutter rangeof stimulus frequencies.


FIG U RE 3. Responsivity (in terms of average spikes/cycle) and entrainment (in terms of rb ) for the same neuron and afferent (Figs. 1 and2) plotted as functions of trial number and time in seconds after stimulus onset.

FIG U RE 4. Relationship between mean firing rate and stimulus frequency for the same neuron (top) and afferent (bottom) whose data areshown in Figures 1–3.

A property common to the great majority of therecordings of SI RA neuronal activity was thatMFR did not reliably increase as stimulus fre-quency increased over the range 50–200 Hz. Formany such recordings, in fact, a 10–20 Hz increasein stimulus frequency at frequencies > 50 Hz wasaccompanied by a substantial decrease in MFR. Inaddition, in most cases the initial rate of stimulus-evoked spike firing failed to be maintained overeven relatively brief (0.5–2 sec) periods of constanthigh-frequency stimulation. The SI neuron whosedata are shown in Figures 1–4 is atypical in thisregard, and the phenomenon is considerably moreobvious in the results obtained from other neurons.For example, the single RA neuron whose data areshown in Figure 5 emitted well-maintained and

well-entrained spike discharge in response to 10 Hzstimulation (plots at top), but its responses to same-site 50 Hz (middle) or 100 Hz stimulation (bottom)were neither well-maintained nor well-entrained. Atthe two higher frequencies of stimulation this neu-ron’s response in the initial 100 msec after stimulusonset either approximates (at 50 Hz) or exceeds(at 100 Hz) its response to 10 Hz. However, withcontinuing stimulation at 50 Hz MFR declinedprogressively from its initial values, and at 100 Hzfiring rate fell below background for a brief period,and then resumed at a rate much lower than thatevoked by 10 Hz stimulation.

Figure 6 shows the pronounced frequency-depend-ency of another SI RA neuron. This neuron, like the SIneurons shown in Figures 1–5, responded vigorously


FIG U RE 5. Spike trains (rasters at left), PSTs (middle), and circular histograms (right) for RA SI neuron in lamina III of area 3b (cat). TheRF included digit pads 2–4 as well as neighboring regions of hairy skin on the ventral surfaces of digits 2–4. Three frequencies of stimulationof the digital pad of digit 3 were delivered (10 Hz, top; 50 Hz, middle; and 100 Hz, bottom). At all frequencies amplitude = 500 m m;duration = 800 ms; ISI = 2 s; probe diameter = 5 mm. The responses to 33–37 presentations of each frequency were recorded. Meanfiring rate (calculated over the entire 800 ms period of stimulation) at 10 Hz was 24.76 spikes/s, SD = 7.00; at 50 Hz, 17.23 spikes/s, SD= 6.40; and at 100 Hz, 18.01 spikes/s, SD = 5.02. Average rate of spike discharge in the absence of stimulation was 7.66 spikes/s (arrowson PST ordinates).

and in a sustained manner to each of the six mid-rangefrequencies of flutter stimulation that were delivered(only the PSTs for the responses to 7 and 20 Hzstimulation are shown at the top of Fig. 6 due to spacecontraints). In contrast, the response of this sameneuron to each of the five higher stimulus frequencies(50, 60, 70, 95, and 105 Hz) was quite different: ateach of these frequencies there was a burst of spikedischarge activity within the first 50 ms of stimulationthat was followed by either a precipitous slowing orcomplete elimination of spike firing lasting for100–200 ms. Moreover, at every frequency between50 and 105 Hz spike firing resumed with continuingstimulation, but at a rate substantially lower than thatrecorded at the same time after onset of flutterstimulation. Figure 6 also shows that (1) at fre-quencies of 50 Hz or higher, MFR and entrainmentwere substantially lower than at any frequencybetween 7 and 25 Hz, and (2) entrainment droppedprogressively as frequency was increased above 50 Hz

(see circular histograms, MFR vs frequency, andentrainment vs frequency plots in Fig. 6).

OIS/neural recording experiments

“Combined” OIS imaging and extracellular singleneuron recording experiments yielded informationabout why some SI RA neurons (e.g., the neuronwhose data are illustrated in Figs. 1–4) continued todischarge vigorously throughout the application of ahigh frequency stimulus to the RF, while for others(e.g., the neurons in Figs. 5 and 6) MFR fell rapidlytowards or even below background shortly after theonset of high-frequency stimulation.

Figure 7 shows OIS difference images obtainedfrom SI cortex of a cat at two different times (1 and5 s) after the onset of 25 Hz vs 200 Hz stimulation ofthe same skin site. Consistent with the findingsreported in earlier studies (Tommerdahl et al., 1999a,b), the absorbance changes evoked by flutter vs


FIG U RE 6. PST (top) and circular histograms (middle) generated from the spike train responses of area 3b RA neuron (lamina IV) to sevendifferent frequencies. All stimuli were applied to the ulnar edge of the digital pad of contralateral forepaw digit 5 (cat). At all frequenciesamplitude = 200 m m, duration = 800 ms, ISI = 5 s, probe diameter = 5 mm. The responses to at least 40 trials were recorded at eachstimulus frequency. Plots at bottom show MFR and rb as functions of frequency.

vibratory stimulation were quite different: whereasabsorbance at all loci within the topographicallyappropriate region increased rapidly and tended toremain at levels well above background throughoutthe full 5 s period of 25 Hz stimulation, with 200 Hzstimulation absorbance increased at most of the sameloci during the initial 1 s of stimulation, but thendeclined rapidly towards background. Several spa-tially discrete zones located within the relativelyextensive region that responded to 25 Hz wereexceptional, however, in that absorbance in theseregions remained at above-background valuesthroughout the full 5 s period of 200 Hz stimulation.

Since absorbance and neuronal spike dischargeactivity are highly correlated, we anticipated that RAneurons in the regions of SI that exhibited asustained increase in absorbance in response to both25 and 200 Hz stimulation would respond with asustained increase in MFR to both frequencies, andthe responses of RA neurons in regions of SI whichyielded a sustained increase in absorbance to 25 Hz,but not to 200 Hz, would be correspondingly differ-ent. For the experiment illustrated in Figure 7, thespecific expectation was that RA neurons encoun-tered in Penetration #1 (circle with crosshairslabeled “1” in panel at right) would be vigorously


FIG U RE 7. Bottom left panel—photograph showing superficial vasculature in pericoronal cortex (cat), entry points of three microelectrodepenetrations ( 3 ), and boundaries of cytoarchitectonic areas 3b and 3a (heavy black lines). CS = coronal sulcus. Top row, two panels atleft—difference images showing absorbance increase at 1 s after onset of 25 Hz (left) or 200 Hz (2nd from left) stimulation, respectively, ofthe contralateral pisiform pad. At both frequencies stimulus amplitude = 100 m m, ISI = 10 s, probe diameter = 5 mm. Pixel darknessindicates magnitude of the stimulus-evoked increase in absorbance. Middle row, two panels at left—images showing absorbance increaseat 5 s after onset of 25 Hz (left) and 200 Hz (2nd from left) stimulation. Image orientation indicated by axes at bottom (L = lateral; A =anterior; M = medial; P = posterior). Figurine of forelimb at bottom right indicates (filled dot, arrow) stimulated skin site. Bottom row,2nd panel from left—plot at same magnification as OIS images that identifies regions in which absorbance values were largest (upper 5%)at 5 s after onset of 25 Hz (gray regions) or 200 Hz (black regions) stimulation. Panel at right: same contour plot described above, at highermagnification (in this panel the regions of maximal absorbance increase at 5 s after onset of 25 Hz and 200 Hz stimulation are outlined bygray and black lines, respectively). Top right—drawing of coronal section depicting entry points (arrows with numbers) of microelectrodepenetrations 1–3, and sites (lines perpendicular to each track) at which RA neuron spike discharge activity was recorded. Line to right ofa track indicates a site where both 25 Hz and 200 Hz vibrotactile stimulation of the pisiform pad evoked above-background activitythroughout the 5 s stimulus period. Line to left of a track indicates a site where 25 Hz, but not 200 Hz stimulation, evoked above-background activity throughout the 5 s period of stimulation. Gray shading shows approximate locus of region in which RA neuronsexhibited a sustained increase in absorbance in response to both 25 Hz and 200 Hz stimulation of the pisiform pad. Sustained, above-background RA neuron spike discharge activity was detected consistently in this region during both 25 Hz and 200 Hz stimulation of thepisiform pad, whereas only 25 Hz stimulation yielded consistent responses in the regions traversed by penetrations 2 and 3.

activated throughout the full period of either 25 or200 Hz stimulation of the RF, whereas the RAneurons recorded in either Penetration #2 or Pene-tration #3 would exhibit well-sustained, above-background spike discharge activity in response to25 Hz stimulation, but not to 200 Hz stimulation.

The PST histograms in Figures 8–10 show thedetailed form of the MFR responses to 25 Hz and to200 Hz stimulation at each site at which SI RAneuron activity was studied during the three micro-electrode penetrations shown in Figure 7; and thecircular histograms in the same figures reveal thedegree to which each response was entrained. Theseresults are viewed as generally consistent with theprediction: that is, the response of almost every SIRA neuron/neuron cluster sampled in these threepenetrations was robust, well maintained, and wellentrained when the frequency of stimulation was

25 Hz, but vigorous, sustained, whereas entrainedspike discharge activity to 200 Hz stimulation wasespecially evident when the microelectrode encoun-tered neurons within a SI region that displayed asustained increase in absorbance during 200 Hz(e.g., Penetration #1).

The findings in Figures 8–10 (and the similarfindings obtained in the three other experiments ofthis type) demonstrate that although RA neuronslocated in nearby SI cell columns may react in a verysimilar way to flutter stimulation, their responses tohigh-frequency stimulation of the same skin site canbe very different. Specifically, these results supportthe idea that the focal, and usually multiple SIregions that exhibit increased absorbance throughoutthe full period of 200 Hz stimulation are occupied byRA neurons whose MFR remains substantially abovebackground during 200 Hz stimulation (e.g., PSTs


FIG U RE 8. PST and circular histogram pairs generated from the spike train data recorded at seven sites in penetration 2 of Figure 7. Thetop–bottom sequence of PST/circular histogram pairs preserves the superficial-to-deep order of the sites at which RA neuron activity wasstudied. The first five recordings were made at successively deeper locations within layer III (between 0.25 and 0.6 mm from the pialsurface); the last two in layer IV (between 0.65 and 0.85 mm).

in Penetration #1; Fig. 9), and that for the RAneurons in the much larger region that undergoes atransient increase in absorbance during 200 Hzstimulation of the same skin site MFR (1) increasestransiently, (2) collapses to a near- or below-background level, (3) remains either at below-background or at near-background levels for as longas the 200 Hz stimulus continues, and then (4)elevates (“rebounds”) transiently upon stimulustermination (e.g., PSTs obtained in Penetration #2;Fig. 8).

We sought to evaluate the above interpretation bystudying the effects of a change in stimulus positionwithin the RF on the spike train responses evokedfrom the same RA neuron by flutter vs vibratorystimulation. Our rationale was that a shift in theplace of stimulation relative to the RFcenter should beaccompanied by a systematic modification of the

frequency dependency of the RA neuron response tovibrotactile stimulation. That is, it was expected thatwhen a vibrotactile stimulus is delivered to theRFcenter the spike discharge activity that it evokes willbe relatively well maintained and entrained to bothflutter (6–50 Hz) and vibration (50–200 Hz), andalthough the activity evoked by flutter stimulationwill remain relatively well maintained and entrainedas distance between the stimulus site and the RFcenter

is increased, that evoked by vibration will not.The representative results shown in Figure 11 were

obtained from an RA neuron in area 3b (lamina III).This neuron responded with vigorous spike dis-charge activity when each frequency of stimulationwas applied to its RFcenter , and at each of the fivestimulus frequencies (12, 15, 50 100, and 150 Hz)the rate of spike firing declined only modestly overthe 2 s stimulus period. In contrast, when the


FIG U RE 9. PST and circular histogram pairs generated from the data recorded at five sites in penetration 1 of Figure 7. Format as in Figure8. The first two recordings were made in layer III (between 0.7 and 0.75 mm from the surface); the next in layer IV (at 0.8 mm); and thelast two recordings in layer V (between 0.85 and 0.95 mm).

stimulator probe (5 mm diameter) was repositionedso that it was centered on a skin site 8 mm away fromthe RFcenter , only frequencies of stimulation withinthe flutter range (compare PST histograms on leftand right) evoked vigorous and relatively well-sustained spike discharge activity.

The data in Figure 11 (and the data from fourother SI RA neurons studied in the same way)support our interpretation of the findings obtainedin the OIS imaging/neurophysiological recordingexperiments. Taken together, the observationsobtained in combined imaging/neurophysiologicalrecording experiments and in studies of the effectsof changes in the position of vibrotactile stimulationwithin the RF strongly suggest that: (1) 200 Hzstimulation evokes a vigorous and relatively well-sustained response from only a small subset of the

RA neurons within the large SI region that res-ponds vigorously and in a sustained manner tosame-site 25 Hz flutter; and (2) the RA neuronsthat do respond in this way to 200 Hz stimulationare those in which the RFcenter coincided with thestimulated skin site.

Results of statistical analyses

Statistical analyses performed on the entire RA SIneuron and RA afferent databases confirmed andextend the exemplary findings illustrated in Figures1–11. Figure 12A summarizes results regardingthe relationship between responsivity and stimulusfrequency for both the RA afferents and SI neu-rons, using measures of responsivity for the 0–0.5and 0–2 s periods after stimulus onset. For the


FIG U RE 10. PST and circular histogram pairs generated from the data recorded at five sites in penetration 3 of Figure 7. Format as in Figure8. The first recording was obtained in layer IV (0.96 mm from the surface); the others in layer V (between 1.0 and 1.3 mm). Interestingly,at two sites in layer III in this penetration (not shown) RA neuron MFR was observed to increase during 25 Hz stimulation and drop tobelow-background levels during 200 Hz stimulation, but substantial entrainment of spike discharge activity occurred in response to bothstimulus frequencies.

afferents, average responsivity is less than one spikeper cycle throughout the entire range of stimulusfrequencies, and although there appears to be somedecline of responsivity at the higher frequencies,these differences are small and statistically insignif-icant. Compared to RA afferents, SI neuronsshowed generally much higher responsivities, and asharp decline in responsivity concentrated primarilyin the flutter range of frequencies. In Figure 12A,which was constructed using only the data obtainedin runs in which stimulus amplitude was 100 m m,this effect is highly significant (for 0–0.5 s, 6 F168 =23.3, p < 10– 6; and for 0–2 s, 6 F168 = 21.2, p <10– 6 ). Furthermore, orthogonal-polynomials analy-sis reveals that the overall effect is dominated by thelinear component of the downward trend. The samepattern appears in the complete RA SI neuron

database, and also in separate analyses of its majorsubgroupings, in particular in cats vs monkeys, andin SUR vs MUR.

Another noteworthy feature of Figure 12A is thatmean responsivity of both RA afferents and SIneurons over the period 0–2 s after stimulus onset isconsistently lower than mean responsivity measuredduring the period 0–0.5 s. This rapid drop in respon-sivity is, in fact, independently significant, overall, forboth afferents and SI neurons. For the RA afferentsthe mean difference is 0.096 spikes/cycle, t102 =7.43, p < 10– 6, while for SI neurons it is 0.462, t323

= 14.1, p < 10– 6. Moreover, as shown in Figure12B, for SI neurons but not RA skin afferents therapid drop in responsivity is itself highly frequency-dependent, again being more pronounced at lowerstimulus frequencies. The overall ANOVA is highly


FIG U RE 11. Effects of stimulus frequency on the activity evoked at two different sites in the RF of the same area 3b RA neuron. Responseswere evoked using stimuli 2 s in duration applied using a 5 mm probe. The RF included contiguous portions of the first and secondinterdigital pads on the volar foot (macaque monkey). PSTs on left were obtained by stimulating at the RFcenter (the distal tip of the firstinterdigital pad), PSTs on right were obtained by stimulating at an off-RFcente r site (at the center of the second interdigital pad). Center-to-center distance between the two sites was 8 mm.

significant (6 F168 = 19.5, p < 10– 6 ), and this isagain driven primarily by the linear component of themonotonic decrease with increasing stimulusfrequency.

To characterize the overall statistical associationbetween vibrotactile stimulus frequency and thetendency (illustrated in Figs. 5, 6, and 9) for the meanfiring rate of many, but not all SI neurons to eitherapproach or fall below background levels (“collapse”)shortly after the onset of stimulation, every run of SIneuron activity was categorized by eye as displaying ornot displaying that phenomenon, and the resultscross-tabulated against stimulus frequency. As shownin Table 2, the overall association is highly significant( x 2

6 = 141.2, p < 10– 6 ), and it takes the specific formof a progressive increase in the proportion of units thatexhibit mean firing rate “collapse” with increasingstimulus frequency (Cochran’s test of linear trend =109.3, df = 1, p < 10– 6 ).

Figure 12C shows that while average RA afferentMFR increases significantly and nearly linearly withstimulus frequency (as implied by the periodicityhypothesis—Talbot et al., 1968), average SI RAneuron MFR increases only up to about 25 Hz, withhigh variability, and either remains level or declinesat higher frequencies.

The average effects of vibrotactile frequency onSI RA neuron and RA afferent entrainment aresummarized in Figure 12D. RA afferent entrain-ment is uniformly high and stable to at least100 Hz, and declines only slightly at 150 Hz. Theoverall ANOVA for frequency is significant (4 F83 =5.3, p < 0.001), a result due entirely to the slightdroop in rb at 150 Hz, and to the extremely lowvariabilities associated with RA afferent rb at allstimulus frequencies. Variances for SI RA neuronsare almost ten times larger than the variances forRA afferents (itself a statistically significant differ-ence), but even this relatively high variability cannotmask the large and systematic dependence of SI RA

neuron entrainment on stimulus frequency. For theSI neuron entrainment vs frequency data shown inFigure 12D, 6 F168 = 43.4, p < 10– 6, and thisresult is again due primarily to the linear compo-nent of the downward trend. As in the case of theeffects of stimulus frequency on responsivity, thesame basic patterns appear both in the completedatabase and in separate analyses of its majorsubgroups such as cats vs monkeys and SUR vsMUR. In particular, the relationship is of the sameform for the SUR data by itself, but statistically it iseven stronger because the variance associated withSURs is typically less than half the variance asso-ciated with MURs.

Figure 12D also makes it apparent that for SI RAneurons mean rb approaches zero at high stimulusfrequencies, and the relatively shapeless circularhistograms typically obtained at such frequencies(Fig. 2, left; Figs. 5 and 6) likewise provide littleassurance that meaningful degrees of entrainment areactually present. Surprisingly, however, even at150 Hz average SI RA neuron rb is significantlygreater than zero (t1 8 = 7.71, p < 0.0001).Moreover, the power spectra of the resampled andtime-averaged spike trains provide clear, direct andcompelling evidence that partial frequency-followingresponses do occur in some SI RA neurons atfrequencies of 100 Hz and higher. Figure 13, forexample, shows the spectra of MUR recordingsobtained during two microelectrode penetrations (#1and #2) that traversed area 3b in monkey SI cortex. Inboth cases sinusoidal stimuli of 100 m m peak-to-peakamplitude were presented at five different frequenciesin randomized order. At every frequency a sharp peakin power is evident at the stimulus frequency and at itslow harmonics (multiple harmonics are especiallyapparent at the lower frequencies), while the totalharmonic response becomes generally smaller athigher frequencies, in parallel with the aggregatestatistical behavior shown in Figure 12D. These peaksin power, which are well above the noise background,can derive only from subsets of spikes that occur atconsistent positions in the stimulus cycle, andtherefore they reflect corresponding degrees ofentrainment in the neuronal response.1

Extracellular microelectrode recording observa-tions paralleling the OIS imaging observationsdescribed in the Introduction were made in fivedifferent experiments, yielding 62 recordings of SIRA neuron activity evoked by 25 Hz vs 200 Hz


TA BL E 2. Association between non-maintenance of MFR (‘‘collapse’’) and stimulus frequency

Stimulus frequency (Hz)

6 12 25 50 100 150 200

Collapse No 15 30 74 6 1 2 6Yes 0 9 31 34 32 17 56

TA BL E 3. Number and proportion of runs in which the r1,r2, or rs measure yielded the highest value of RA neuronentrainment

r1 r2 rs Total

n 141 16 167 324*% 43.5 4.9 51.5

*For 2 of the 326 runs r1 = rs

stimulation delivered to the same skin site. Thirty ofthe 62 recordings (48.4%) were obtained from the“upper layers” (from layer II or the upper half oflayer III), 24 (38.7%) from the “middle layers” (thelower half of layer III or layer IV), and the remaining8 (12.8%) from the “deep layers” (layers V or VI).Each of the two frequencies of stimulation waspresented 10–20 times. Figure 14 provides twoexamples of unambiguous SI RA neuron entrain-ment by 200 Hz stimulation, one a MUR (bottom)and the other a SUR (top). Note again, the co-existence of a sharp spectral driving response at200 Hz stimulation and a rather diffuse and unim-pressive-looking circular histogram. As in all othercases examined, this spectral response appearedwithin the first 250 ms following onset of 200 Hz

stimulation, and persisted for the full period ofstimulation (5 s for the data in Fig. 14).

To underscore the physiological orderliness of themeasured 200 Hz entrainment responses, Figure 15provides a scatter plot of rb at 200 Hz vs rb at 25 Hzfor all 62 of these recordings. For the entire group thePearson r is 0.421, x 2

1 = 11.6, p < 0.001. The plotshows that RA neurons (or small groupings of RAneurons) which entrained relatively well to the200 Hz stimulus invariably entrained relatively wellto the 25 Hz stimulus, while the converse was lessconsistently true. That is, consistent with the discus-sion of Figures 8–11, good SI RA neuron entrain-ment by flutter stimulation is a necessary but notsufficient condition for entrainment by vibration.There was a marginally significant tendency (2 F5 8 =


FIG U RE 12. Frequency dependence of average responsivity and entrainment—ANOVA results. All plots show means over all units; errorbars indicate ± 1 SE. (A) Frequency dependency of SI RA neuron and RA afferent responsivity (measured in terms of spikes/cyclemeasured at 0–0.5 s and at 0–2.0 s after stimulus onset). (B) Frequency dependency of the decrease in SI RA neuron and RA afferentresponsivity that occurred between 0–0.5 s and 0–2.0 s after stimulus onset. (C) Frequency dependency of average normalized SI RAneuron and RA afferent mean firing rate for two time periods (0–0.5 s and 0–2.0 s) after stimulus onset. MFR for each recording/conditionwas expressed as a fraction of the maximum average MFR observed over the entire sample at that condition, and these normalized MFRswere, in turn, averaged. (D) Frequency dependency of average SI RA neuron and RA afferent entrainment.

3.601, p = 0.0336) for RA neuron entrainment at200 Hz to be higher for recordings from “middlelayer” neurons than for recordings from either“upper” or “deep” layer neurons.

Discussion

RA skin afferent behavior

Most previous studies of RA afferent response tovibrotactile stimulation, including our own recentstudy (Whitsel et al., 2000), focused primarily onstimulus frequencies in the flutter range (10–50 Hz).The main consequence of the new findings reportedhere, in combination with results already in theliterature, is to underscore that RA afferents are

highly responsive to, and well entrained by high-frequency vibrotactile stimuli.

Our results concerning RA afferent responsivityare very similar to those of Johansson et al. (1982),who reported detailed microneurographic studies ofeight human RA afferents innervating the glabrousskin of the hand (see their Fig. 2). Both our studyand the study of Johansson et al. (1982) found thatRA afferent responsivity was slightly less than onespike per cycle at low frequencies for sinusoidalstimuli of 100–200 m m peak-to-peak amplitude,declining slowly to around 0.5 spikes/cycle at150 Hz. The Johansson et al. (1982) data indicate,moreover, that this same low level of responsivity ismaintained to at least 400 Hz.


FIG U RE 13. Power spectra for the activity evoked from two multi-unit recordings of RA SI neuron spike discharge activity. The data wererecorded at different sites in lamina III in area 1 of the same subject (macaque monkey). The data that yielded the spectra on the right wereevoked by 15 presentations of each frequency. Probe diameter was 2 mm; stimulus amplitude 100 m m; stimulus duration 2 s. The spectraon the left were obtained from the activity evoked by 20 presentations of each frequency. Probe diameter was 5 mm; stimulus amplitude100 m m; stimulus duration 2 s. For both recordings the RF was located on the medial interdigital pad on the foot. Each spectrum has beennormalized relative to its maximum ‘‘power’’ (in normalized spikes2 /Hz). The overall decline in entrained spike activity with increasingfrequency is reflected both in the declining values of rb and in the relative increase in background power at higher stimulus frequencies.

The temporal organization of the high-frequencyresponse of RA afferents has not previously beenexplicitly characterized, but it can be inferred fromdata presented by Talbot et al. (1968) showing thatby increasing stimulus amplitude sufficiently, manyRA afferents can be driven onto the “tuning pla-teau” (where they discharge approximately onespike per stimulus cycle at essentially the samephase) at frequencies up to at least 300 Hz (seetheir Figs. 12, 20, 21, and especially 22). Ourresults explicitly confirm, using the measurementtools introduced in Whitsel et al. (2000), that thepowerful entrainment of RA afferents observed atflutter frequencies extends smoothly and virtuallyunchanged to frequencies in the vibration range.The slight loss of overall responsivity (Fig. 12A),coupled with the increasing tendency at higherstimulus frequencies for the RA afferent response todecline late in a trial and late in a run (see Fig. 1),means that at a high frequency of stimulationindividual RA afferents may fail to fire spikes onmany stimulus cycles. Nevertheless, even in thesesparsely populated regions of the response, thespikes that do occur maintain a consistent phase-locked relationship to the stimulus cycle. The rela-tively secure, short-latency convergence of the cen-tral projections of RA afferents onto their SItargets, by itself, makes it likely that partial entrain-ment responses can occur in SI RA-type neurons athigh stimulus frequencies, just as these same neu-rons can be entrained by flutter stimuli at ampli-tudes insufficient to produce 1 : 1 entrainment ofsingle RA afferents (Mountcastle et al., 1969).

SI RA-type single neuron/neuron population behavior

In sharp contrast to RA afferents, both the respon-sivity and entrainment of SI RA neurons are promi-nently frequency-dependent.

Responsivity, and its relationship to OIS results Theoverall responsivity of SI RA neurons at flutterfrequencies (10–50 Hz) is far higher than that of the


FIG U RE 14. Two examples of SI RA neuron entrainment by 200 Hz stimulation. Both recordings were obtained in the OIS imaging/neurophysiological recording experiment (cat) illustrated in Figure 7. The spike train data that yielded the spectrum and circular histogramat the top were recorded from a single layer V area 3b in response to 20 presentations of a 100 m m amplitude, 5 s 200 Hz stimulus (5 mmprobe) to the pisiform pad of the contralateral forepaw. The spectrum and circular histogram shown at the bottom were generated frommulti-unit RA neuron activity evoked by the same stimulus in area 3b, layer IV.

FIG U RE 15. Entrainment at 200 Hz vs entrainment at 25 Hz for all62 SI RA neurons studied using both 200 Hz and 25 Hzstimulation. For each recording stimulus duration = 5 s; ISI =15 s, probe on RFcenter , amplitude = 100–600 m m, frequenciesinterleaved.

individual RA afferents which are the principal (ifnot the sole) peripheral source of their short-latencyafferent drive. This presumably reflects not only thefact that the central projections of many RA afferentsconverge onto single SI neurons, but also the factthat each SI neuron is situated in a dense network ofhighly interdependent units and probably receivesthe bulk of its input from other cortical neurons,rather than directly via the central projections ofperipheral afferents.

SI RA neurons exhibit a relatively large overall(across the entire stimulus period; > 80%) loss ofresponsivity with increasing frequency, and this lossis concentrated within the flutter range of stimulusfrequencies (Fig. 12A). They also exhibit a relativelylarge loss of responsivity between the first 0.5 s andthe first 2 s following stimulus onset, and much ofthis loss also occurs within the flutter range (Fig.12B). At frequencies above 100 Hz the responsivityof SI RA neurons approaches that of RAafferents.

The major difference between the time course ofresponsivity of most SI RA neurons at 25 Hz vs200 Hz (relatively constant at 25 Hz vs rapidlydeclining at 200 Hz) is consistent with, and offers anexplanation for the rapid decline in the magnitude ofthe optical sign of SI cortical activation (the increasein absorbance) during 200 Hz stimulation. Althoughthis decline undoubtedly reflects, in part, theobserved loss in RA afferent drive that accompanieshigh-frequency skin stimulation, additional featuresobserved in SI RA neuron spike train responses areconsistent with the finding (Tommerdahl et al.,1999a, b) that during 200 Hz stimulation OISabsorbance in a large territory that surrounds theactivated SI region often declines to levels below thosemeasured prior to skin stimulation. That SI neuronsat off-focus locations are subjected to some degree offrequency-specific inhibition is suggested by severalcharacteristics commonly observed in the spikedischarge activity of the RA neurons in these regionsduring high-frequency stimulation—in particular, bythe increasing tendency of MFR to “collapse”following stimulus onset with increasing stimulusfrequency (Table 2), by the prominent “rebound”increase in MFR that often occurs at stimulus offset,by a period during stimulation when MFR goesbelow background, and by burst-like spike dischargeactivity during stimulation (all these phenomena arerevealed by the PST histograms obtained using200 Hz stimulation; Figs. 4–6). This suggestion alsois supported by the finding that these same charac-teristics become more prominent when the high-frequency stimulus is moved to a skin site that doesnot include the RFcenter (Fig. 11).

The effects of high-frequency stimulation on thespike discharge activity of individual SI RA neurons orlocal neuronal groupings (Figs. 1–7), and on thespatial distribution of SI optical activity (Fig. 7; alsosee Tommerdahl et al., 1999a, b) parallel recent

observations in rat barrel cortex (Brumberg et al.,1996; Sheth et al., 1998), and older descriptions of theresponse of individual SI neurons in monkeys(Renkin, 1959) and the SI population response in cats(Dewson, 1964). Brumberg et al. (1996) reportedthat (1) low-amplitude, high-frequency sinusoidalwhisker motion consistently inhibits the spike dis-charge response of regular-spiking barrel neurons toramp-and-hold movements of the principal whisker,and (2) the inhibition is greatest when the high-frequency whisker motion is “same-site” (i.e., appliedto the same whisker that received the ramp-and-holdstimulus). At the neural population level, Sheth et al.(1998) demonstrated, using a combination of in vivoOIS imaging and neurophysiological populationrecording methods, that the rat barrel cortical regionactivated by low-frequency stimulation of one or a fewvibrissae is spatially more diffuse and widespread thanthe territory activated at higher stimulus frequencies.While Sheth et al. (1998) favored explanation of theirresult in terms of a differential activation of twosystems of thalamocortical projections with differentfrequency-following characteristics, they did notreject the possibility that a frequency-dependentcortical inhibition was involved. The results obtainedin in vitro OIS imaging studies of the rat barrel cortexslice (Tommerdahl et al., unpublished observation)are relevant because they have demonstrated thathigh-frequency electrical stimulation at a site in thewhite matter immediately underlying layer VI isaccompanied by a prominent spatial sharpening of thecolumn-shaped optical response of the slice to lowerfrequency stimulation of the same layer VI site—anoutcome that strongly suggests that cortical inhibitorymechanisms are selectively evoked by high-frequencyinput. Renkin (1959) demonstrated that SI neuronsthat were activated by hair movement (presumablyRA neurons) gave sustained spike discharge activity inresponse to a 200 Hz electrical stimulus when thestimulation was delivered to the RFcenter , while high-frequency electrical stimulation at an off-centerposition in the RF produced a response at stimulusonset and often failed to elicit sustained spikedischarge activity. Similarly, Dewson (1964) usedneurophysiological population recording methods todemonstrate that 200 Hz vibration evoked a spatiallyless extensive SI response than the one evoked bysingle pulse stimulation of the same skin site. Humanpsychophysical studies also have provided evidenceconsistent with inhibitory effects of high-frequencyskin stimulation on both the magnitude and spatialdistribution of SI activity evoked by cutaneous flutterstimulation. For example, Ferrington et al. (1977)demonstrated that coincident high-frequency(300 Hz) vibrotactile stimulation of the thenar emi-nence substantially elevates the threshold at whichhumans detect cutaneous flutter (30 Hz) at the tip ofthe index finger of the same but not the opposite hand;and Vierck and Jones (1970) showed that thethreshold for discriminating two points applied


simultaneously to closely spaced skin points issignificantly lowered when the two points are oscillat-ing at 300 Hz.


Entrainment, and its relation to cortical mechanisms offrequency discrimination A major goal of the presentinvestigation was to extend the seminal work ofMountcastle et al. (1969) by providing a morecomplete and quantitative characterization of thefrequency-dependent entrainment behaviors of RA-type SI cortical neurons. Mountcastle et al. (1969)approached this task by transposing to the corticallevel the tuning-plateau model first introduced byTalbot et al. (1968) in their comprehensive study ofthe mechanoreceptive afferents of the glabrous skinof the monkey hand. Using 80% entrainment as their“tuning criterion” (i.e., when 80% of stimulus-evoked spikes occur within an optimally positionedtime window one-half stimulus cycle in length),Mountcastle et al. (1969) showed that entrainment ispresent in SI RA neurons throughout the flutterrange, with an apparent maximum between 20 and40 Hz. This finding provided the basis for the onceuniversally accepted “periodicity hypothesis” for SIcortical encoding and discrimination of the fre-quency of cutaneous flutter stimulation (see alsoLaMotte and Mountcastle, 1975; Mountcastle,1984; Mountcastle et al., 1990). The neural basis forfrequency discrimination within the range of fre-quencies experienced as vibration remained uncer-tain, however, because Mountcastle and his col-leagues found little or no evidence for entrainment ofSI neurons by stimulus frequencies above 60–80 Hz,either in RA or in PC (Pacinian) pyramidal neurons.They did, however, find entrainment at high stim-ulus frequencies in SI neurons with “thin spikes”(Mountcastle et al., 1969; a characteristic nowbelieved unique to the GABAergic local inhibitoryinterneurons of sensory cortex; McCormick et al.,1985), confirming that vibratory stimuli evoke peri-odic high-frequency afferent drive that reaches SI.

The techniques introduced in Whitsel et al. (2000)enable, for the first time, quantitative measurementof the degree of entrainment present in the spiketrains of RA SI neurons, independent of responsivity.Figure 12D demonstrates, in a fully quantitativemanner based on a large sample of units, that RA-type SI neuron entrainment is strongly and system-atically frequency-dependent. There are, however,two surprising features: first, the frequency tuningcurve for RA-type neurons does not peak in themiddle of the flutter range, but is maximal at thelowest frequencies (where SI RA neuron entrainmentapproaches that of the RA-I afferents) and declinesmore or less monotonically with increasing stimulusfrequency. Second, and more surprising and inter-esting, is the finding that meaningful levels of RA SIneuron entrainment can be detected and measuredout to frequencies at least as high as 200 Hz (Figs.13–15).

Figures 13–15 show that (1) the spike dischargeactivity evoked from SI RA neurons is partiallyentrained by high-frequency stimulation, and (2) thisdegree of entrainment persists with continuing stim-ulation despite the fact that the firing rate of many ofthese neurons declines rapidly (“collapses”) to nearor below-background levels within a short time(0.5–2 s) after stimulus onset. These observationssuggest, contrary to previous thinking, that low levelsof periodic firing in the responding population of SIRA neurons could contribute importantly to, andmay even account for, frequency discriminationwithin the range of frequencies experienced asvibration. That is, the periodicity hypothesis of SIcortical frequency coding may actually hold through-out, and perhaps even beyond, the range of fre-quencies (6–200 Hz) studied in our experiments.The possibility that SI RA neuron activity mightcontribute to the perception of stimulus frequenciesexperienced as vibration would be consistent withthe demonstration, using near-threshold intraneuralmicrostimulation (Torebjork et al., 1987), that thesensations evoked by stimulation of the same RAafferent at different frequencies are qualitativelydifferent: frequencies of RA afferent stimulation< 20 Hz are reported as “tapping”, frequenciesbetween 20 and 50 Hz as “flutter”, and frequencies> 50 Hz as “vibration/buzzing”.

The idea that periodicity in SI RA neuron spikedischarge activity might also account for the capac-ity to discriminate stimulus frequency at frequen-cies > 50 Hz is directly supported by the closerelationship between our SI RA neuron entrainmentresults and existing data on human frequency dis-crimination, summarized in Figure 16. This figureshows the published human psychophysical differ-ence limens in the form of frequency differencesbetween standard and comparison stimuli ( D f ’s) asa function of the frequency of the standard stim-ulus. Following Mountcastle et al. (1969), we usedour measures of the temporal variability of spikeposition in the stimulus cycle to estimate D f at eachfrequency of stimulation. Whereas Mountcastle etal. (1969) used temporal standard deviations calcu-lated from cycle histograms, we first converted eachmeasured rb to the equivalent circular-statisticsmeasure of variability, the angular standard devia-tion 180

p Î (2(1–rb ); Batschelet, 1981). This result wasdivided by 360°, and multiplied by the base stim-ulus frequency to derive an estimated frequency D f.For the RA neuron recordings this procedure wascarried out using both run-by-run values of rb andmean values of rb , yielding nearly identical results.In both cases the values of D f estimated from rb

coincide almost perfectly with the psychophysicalvalues of D f obtained by Mountcastle et al. (1969)under similar stimulus conditions (Fig. 16), andoccupy an intermediate position between the resultsof Mountcastle et al. (1990; who used highlytrained monkey and human subjects) and those of

Goff (1967; who used relatively inexperiencedhuman subjects). The critical point is that theimproved measures of SI RA neuron entrainmentutilized in the present study closely fit the psycho-physical data of Mountcastle et al. (1969), and doso not only over the range of frequencies humansexperience as cutaneous flutter (5–50 Hz), but alsoat those higher frequencies (60–200 Hz) experi-enced as vibration (Fig. 16).

In sum, the entrainment results obtained in thepresent investigation not only provide additionalsupport for the original periodicity hypothesis offrequency coding by SI RA neurons, as formulatedby Mountcastle et al. (1969), but suggest its possibleextension to the range of frequencies experienced asvibration. There are several obstacles, however, tosuch a major extension: first are unpublished resultsby Merzenich and Harrington which Mountcastle etal. (1969, 1990) describe as demonstrating thatcomplete local anesthesia of the glabrous skin of thehand leaves unimpaired the capacity for frequencydiscrimination at high frequencies of stimulation.This observation, if adequately documented orindependently confirmed, clearly would establish acritical role for the PC system and possibly corticalarea SII, in vibratory frequency discrimination. Onthe other hand, if the entrainment of SI RA neuronscontributes importantly to both flutter and vibratoryfrequency discrimination, complete local anesthesia

of the skin in the vicinity of the stimulus site shouldbe expected to impair, if not completely eliminate,frequency discrimination at all frequencies. Determi-nation of which, if either, of these very differentoutcomes occurs when RA afferents are inactivatedmerits rigorous psychophysical investigation.

The second obstacle is that the literature doescontain evidence suggesting that SII contributes tofrequency discrimination within the range of fre-quencies experienced as vibration. Our own OISimaging studies (Tommerdahl et al., 1999a, b) haveshown that concurrent with the decline in SIactivation during continuing 200 Hz stimulation, SIIactivation not only remains undiminished, but actu-ally increases. Furthermore, published descriptions(e.g., Ferrington and Rowe, 1980; Burton andSinclair, 1991) of the entrainment behaviors of SIIneurons indicate that some SII neurons are entrainedby high-frequency stimuli, and we believe theiractual level of entrainment has been substantiallyunderestimated. The problem is that SII neurons,like PC afferents, tend to emit spike discharges bothduring the advance of a probe into the skin andduring its withdrawal (see, for example, Burton andSinclair, 1991, their Fig. 2; also Ferrington andRowe, 1980, their Fig. 13). The result is a “bipolar”pattern of phase-locked spike discharge that cannotbe adequately quantified (and is grossly under-estimated) using a percent entrainment measure, but


FIG U RE 16. Relationship of SI RA neuron and RA afferent spike entrainment to human psychophysical frequency discriminationperformance. The values of D f estimated from the measures of SI RA neuron and RA afferent entrainment obtained in the present studyare plotted against published measures of human frequency discriminative capacity (Goff, 1967; Mountcastle et al., 1969, 1990). Note thatthe estimate of D f for SI RA neurons increases essentially linearly over the frequency range 6–200 Hz, and that at every frequency withinthis range it corresponds closely to the psychophysical D f reported for human subjects by Mountcastle et al. (1969).

whose temporal order can more accurately be quan-tified using the r2 measure (Batschelet, 1981; Whitselet al., 2000). Until the capacity of SII neurons toentrain to high frequencies of vibrotactile stimulationis more accurately determined, the role of SII incutaneous frequency discrimination at stimulus fre-quencies between 50 and 200 Hz cannot be ade-quately evaluated.

An alternative hypothesis

Finally, we cannot conclude without discussing, atleast briefly, a recent challenge to the periodicityhypothesis in its original form (Romo et al., 1998,2000; Salinas et al., 2000; Romo and Salinas, 2001).These workers, based on results of combined psy-chophysical and neurophysiological investigations inconscious, behaving monkey, have argued that the SIneurons responsible for frequency discriminationwithin the flutter range signal stimulus frequencyprimarily by a mean firing rate code, rather than viathe temporal order of spike firing as specified by theperiodicity hypothesis.

The results of the present investigation, however,combined with related experimental results already inthe literature, undermine the plausibility of thisalternative hypothesis. For example, using only thoseportions of our data obtained under stimulus condi-tions approximating those used by Salinas et al.(2000)—i.e., 100 m m stimulus amplitude; frequen-cies 6, 12, 25, and 50 Hz, mean firing rate sampledover the same time period (0–0.5 s after stimulusonset), we found that SI RA neuron mean firing ratefailed to discriminate even these extremely divergentstimulus frequencies (for the unadjusted MFR 3 F9 2 =1.88, p < 0.138; for adjusted MFR 3 F92 = 1.77, p <0.159). Between 6 and 25 Hz average MFR (acrossneuron MFR) did increase monotonically (Fig. 12C),but the variances associated with these average MFRswere very large, and at 50 Hz average MFR wassmaller than at 25 Hz. This finding reinforces anargument already made by Mountcastle et al. (1990;their Fig. 11) for 17 well-studied RA SI neurons, andpreviously by Mountcastle et al. (1969; their Figs. 4and 5) for 41 additional neurons: specifically, thechanges in MFR observed between closely spacedflutter frequencies that are easily discriminated byboth humans and monkeys are much too small, toovariable, and even too inconsistent in direction toprovide a credible basis for this psychophysicalcapacity. Furthermore, the decline in MFR thatoccurred in virtually all of our SI RA neurons betweenthe periods 0–0.5 and 0–2 s after stimulus onset wasactually larger at higher frequencies; which, in turn,suggests that whatever frequency-dependent differ-ences in MFR may exist shortly after the onset offlutter stimulation would erode as stimulation con-tinues, contrary to the enhancement of discriminativecapacity at frequencies within the flutter range thataccompanies prolonged exposure to flutter stimula-

tion (Goble and Hollins, 1994). Finally, there is aneven more serious objection to the idea that SI RAneurons use a mean rate code to signal and discrim-inate stimulus frequency. This objection, also clearlyrecognized by Mountcastle et al. (1969), is that SI RAneuron MFR is far more dependent on stimulusamplitude than on stimulus frequency.

We conclude, therefore, that as originally proposedby Mountcastle et al. (1969), the entrained spike trainresponses of SI RA neurons provide the mostplausible explanation available for frequency discrim-ination within the range of frequencies subjectsexperience as cutaneous flutter. The entrainmentresults of the present paper further suggest that theexplanatory power of the periodicity hypothesis mayextend to the perceptual discrimination of frequencyat frequencies much higher than 50 Hz, with orperhaps without a contribution from neurons in SII.

Acknowledgements

The authors acknowledge the expert technical con-tributions of Calvin Wong and Carol Metz. Dr K. A.Hester contributed at an early stage of the project asan NIDR Minority Investigator/Trainee supportedby PO1DE07509; W. Maixner, Program Director.The research was funded by NIH grants RO1NS34979 and RO1NS37501 (B. L. Whitsel, P.I.).

Note

1. Readers may notice that the actual peak frequenciesdepart slightly from the nominal frequencies—thisoccurs because in these experiments frequencies weredetermined using a voltage-controlled oscillator to drivethe analog frequency generator. The fundamental fre-quency of the power spectrum always matches exactlythe true stimulus frequency, which can be calculatedfrom the timing markers in the raw digital records.

ReferencesBAT SC H ELET, A. (1981) Circular Statistics in Biology, Academic

Press, London.BRUM BERG , J.C., D.J. PIN TO, and D.J. SIM O N S (1996) Spatial

gradients and inhibitory summation in the rat whisker barrelsystem. J Neurophysiol 76: 130–140.

BRUM BERG , J.C., D.J. PIN TO, and D.J. SIM O N S (1999) Corticalcolumnar processing in the rat whisker-to-barrel system. JNeurophysiol 82: 1808–1817.

BU RT O N , H., and R.J. SIN C LAIR (1991) Second somatosensorycortical area in macaque monkeys: 2. Neuronal responses topunctate vibrotactile stimulation of glabrous skin on the hand.Brain Res 538: 127–135.

CH U BBU CK , J.G. (1966) Small-motion biological stimulator. APLTechnical Digest May–June: 18–23.

DARIA N-SM IT H , I. (1984) The sense of touch: performance andperipheral neural processes, Chapter 17. In: Handbook ofPhysiology—The Nervous System, Vol. 3, pp. 739–788, AmPhysiol Soc, Bethesda, MD.

DEW SO N , J.H. (1964) Cortical responses to patterns of two-pointcutaneous stimulation. J Comp Physiol Psychol 58: 387–389.

FERRIN GT O N , D.G., B.S. NAIL , and M. ROW E (1977) Humantactile detection thresholds: modification by inputs fromspecific tactile receptor classes. J Physiol (Lond) 272:415–433.

FERRIN GT O N , D.G., and M. ROW E (1980) Differential contribu-tions to coding of cutaneous vibratory information by corticalsomatosensory areas I and II. J Neurophysiol 43: 310–331.


FREN C H , A.S., and A.V. HO LD EN (1971a) Alias-free sampling ofneuronal spike trains. Kybernetik 8: 165–171.

FREN C H , A.S., and A.V. HO LD EN (1971b) Semi-on-line imple-mentation of an alias-free sampling system for neuronal signals.Computer Programs Biomedicine 2: 1–7.

GO BLE, A., and M. HO LLIN S (1994) Vibrotactile adaptationenhances frequency discrimination. J Acoust Soc Am 96:771–780.

GO FF, G.D. (1967) Differential discrimination of frequency ofcutaneous mechanical vibration. J Exp Psychol 74: 294–299.

GRIN VA LD, A. (1985) Real-time optical mapping of neuronalactivity: from single growth cones to the intact mammalianbrain. Ann Rev Neurosci 8: 263–305.

GRIN VA LD, A., T. BO N H O EFF ER, D. MALO N EK , D. SH O H AM , E.BARTF ELD, A. ARELI, R. HIL D ESH EIM , and E. RAT ZLAFF (1991)Optical imaging of architecture and function in the living brain.In Memory Organization and Locus of Change, L. SQ UIRE , N.WEIN BERG ER , G. LYN CH , and J. MCGAU GH , eds., pp. 49–85,Oxford University Press, Oxford.

GRIN VA LD, A., E.E. LIE K E, R.D. FRO STIG, and R. HIL D ESH EIM

(1994) Cortical spread-point function and long-range lateralinteractions revealed by real-time optical imaging of monkeyprimary visual cortex. J Neurosci 14: 2545–2568.

GRIN VA LD, A., D. SH O H AM , I. GLASER, A.E. VAN EZET TA , E.SH O TOYERM AN , H. SLOV IN , C. WIJN BERG EN , R. HIL D ESC H EIM ,and A. ARIE LI (1999) In-vivo optical imaging of corticalarchitecture and dynamics. In Modern Techniques in NeuroscienceResearch, U. WIN D H O RST and H. JO H AN SSO N , eds., Chapter 34,pp. 893–969, Springer, New York.

HASSLER, R., and K. MU H S-CLEM EN T (1964) Architektonischeraufblau des sensorimotorischen und parietalen cortex der katze.J Hirnforsch 6: 377–420.

HO LTH O FF, K., and O.W. WIT T E (1996) Intrinsic optical signalsmeasured with near-infra-red dark-field microscopy revealchanges in extracellular space. J Neurosci 16: 2740–2749.

JO H AN SSO N , R.S., U. LAN D STR O M , and R. LUN D ST RO M (1982)Responses of mechanoreceptive afferent units in the glabrousskin of the human hand to sinusoidal skin displacements. BrainRes 244: 17–25.

JO N ES, E.G., and R. PO RT ER (1980) What is area 3a? Brain Res Rev2: 1–43.

KO H N , A., C. MET Z, M. QU IBRERA , M. TO M M ERDA H L, and B.L.WH IT SEL (2000) Functional neocortical microcircuitry demon-strated with intrinsic signal imaging in vitro. Neuroscience 95:51–62.

LAM O T T E, R.H., and V.B. MO UN T C ASTLE (1975) Capacities ofhumans and monkeys to discriminate between vibratory stimuliof different frequency and amplitude: a correlation betweenneural events and psychophysical measurements. J Neurophysiol38: 539–559.

LEU N G , Y.Y. (1994) Adaptation of mechanoreceptive afferents tocontinuous sinusoidal vibration. M.S. thesis, Johns HopkinsUniversity.

LEU N G , Y.Y., S.S. HSIAO, and K.O. JO H N SO N (1994) Adaptation ofmechanoreceptive afferents to continuous sinusoidal vibration.Neurosci Abstr 20: 1381.

MARPLE, S.L., JR (1987) Digital Spectral Analysis with Applications,Prentice-Hall, Englewood Cliffs, NJ.

MCCO RM IC K , D.A., B.W. CO N N ERS, J.W. LIG H T H ALL, and D.A.PRIN C E (1985) Comparative electrophysiology of pyramidal andsparsely spiny stellate neurons of the neocortex. J Neurophysiol54: 782–806.

MCKEN N A , T.M., B.L. WH IT SEL, D.A. DREYER , and C.B. METZ

(1981) Organization of cat SI cortex: relations among cytoarch-itecture, single neuron properties, and interhemispheric con-nectivity. J Neurophysiol 45: 667–697.

MERZEN IC H , M.M., and T. HARRIN GT O N (1969) The sense offlutter vibration evoked by stimulation on the hairy skin ofprimates: comparison of human sensory capacity with theresponses of mechanoreceptive afferents innervating the hairyskin of monkeys. Exp Brain Res 9: 236–269.

MO UN T C ASTLE, V.B. (1984) Central nervous mechanisms in

mechanoreceptive sensibility, Chapter 18. In Handbook ofPhysiology—The Nervous System, Vol. 3, pp. 789–878, AmPhysiol Soc, Bethesda, MD.

MO UN T C ASTLE, V.B., M.A. STEIN M ET Z, and R. RO M O (1990)Frequency discrimination in the sense of flutter: psychophysicalmeasurements correlated with postcentral events in behavingmonkeys. J Neurosci 10: 3032–3044.

MO UN T C ASTLE, V.B., W.H. TALB OT, H. SAK ATA , and J. HYVA RIN EN

(1969) Cortical neuronal mechanisms in flutter vibrationstudied in unanesthetized monkeys. Neuronal periodicity andfrequency discrimination. J Neurophysiol 32: 452–484.

POW ELL, T.P.S., and V.B. MO UN T C AST LE (1959) Some aspects ofthe functional organization of the postcentral gyrus of themonkey: a correlation of findings obtained in a single unitanalysis with cytoarchitecture. Bull Johns Hopkins Hosp 105:133–162.

REN K IN , B.Z. (1959) Response of cortical neurons in the somaticsensory area I of the cat in relation to position and frequency ofelectrical stimulation within cutaneous receptive fields. Doc-toral dissertation, The Johns Hopkins University.

RO M O, R., A. HERN AN D EZ, A. ZAIN O S, C.D. BRO DY, and E.SALIN AS (1998) Sensing without touching: psychophysicalperformance based on cortical microstimulation. Neuron 26:273–278.

RO M O, R., A. HERN AN D EZ, A. ZAIN O S, and L. LEM U S (2000)Somatosensory discrimination based on cortical microstimula-tion. Nature 392: 387–390.

RO M O, R., and E. SALIN AS (2001) Touch and go: decision-makingmechanisms in somatosensation. Ann Rev Neurosci 24:107–137.

SALIN AS, E., A. HERN AN D EZ, A. ZAIN O S, and R. RO M O

(2000) Periodicity and firing rate as candidate neural codes forthe frequency of vibrotactile stimuli. J Neurosci 20:5503–5515.

SH ET H , B.R., C.I. MO O RE, and M. SU R (1998) Temporalmodulation of spatial borders in rat barrel cortex. J Neurophysiol79: 464–470.

SH O H AM , D., and A. GRIN VALD (2001) The cortical representationof the hand in macaque and human area SI: High resolutionoptical imaging. J Neuroscience 21: 6820–6835.

SUR , M., R.J. NELSO N , and J.H. KAAS (1982) Representations ofthe body surface in cortical areas 3b and 1 of squirrel monkeys:comparisons with other primates. J Comp Neurol 211:177–192.

TALBO T, W.H., I. DARIA N-SM IT H , H.H. KO RN H U BER, and V.B.MO UN T C ASTLE (1968) The sense of flutter-vibration: compar-ison of the human capacity with response patterns of mechanor-eceptive afferents from the monkey hand. J Neurophysiol 31:301–334.

TO M M ERDA H L, M., K.A. DELEM O S, B.L. WH IT SEL, O.V. FAVO ROV,and C.B. MET Z (1999a) Response of anterior parietal cortex tocutaneous flutter versus vibration. J Neurophysiol 82: 16–33.

TO M M ERDA H L, M., and B.L. WH IT SEL (1996) Optical imaging ofintrinsic signals in somatosensory cortex. In Somesthesis and theNeurobiology of the Somatosensory Cortex, O. FRAN ZEN , R.JO H AN SSO N , and L. TEREN IUS, eds., pp. 369–384, BirkhauserVerlag, Basel, Switzerland.

TO M M ERDA H L, M., B.L. WH IT SEL, O.V. FAVO ROV, C.B. MET Z, andB. O’QU IN N (1999b) Responses of contralateral SI and SII incat to same-site cutaneous flutter versus vibration. J Neu-rophysiol 82: 1982–1992.

TO REBJORK , H.E., A.B. VALLBO, and J.L. OC H OA (1987) Intra-neural microstimulation in man. Brain 110: 1509–1529.

VALLBO, A.B., K.A. OLSSO N , K.-G. WESTBERG , and F.J. CLARK

(1984) Microstimulation of single tactile afferents from thehuman hand. Brain 107: 727–749.

VIERCK , C.J., JR , and M.B. JO N ES (1970) Influences of low andhigh frequency oscillation upon spatio-tactile resolution. Physi-ology Behavior 5: 1431–1435.

WH IT SEL, B.L., E.F. KELLY, K.A. DELEM O S, M. XU, and P.M.QU IBRERA (2000) Stability of RA afferent entrainment vs.responsivity. Somatosens Mot Res 17: 13–31.


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