Nociceptive afferent activity alters the SI RA neuron response to mechanical skin stimulation.

Procedures that reliably evoke cutaneous pain in humans (i.e., 5-7 s skin contact with a 47-51 °C probe, intradermal algogen injection) are shown to decrease the mean spike firing rate (MFR) and degree to which the rapidly adapting (RA) neurons in areas 3b/1 of squirrel monkey primary somatosensory cortex (SI) entrain to a 25-Hz stimulus to the receptive field center (RF(center)) when stimulus amplitude is "near-threshold" (i.e., 10-50 µm). In contrast, RA neuron MFR and entrainment are either unaffected or enhanced by 47-51 °C contact or intradermal algogen injection when the amplitude of 25-Hz stimulation is 100-200 µm (suprathreshold). The results are attributed to an "activity dependence" of γ-aminobutyric acid (GABA) action on the GABA(A) receptors of RA neurons. The nociceptive afferent drive triggered by skin contact with a 47-51 °C probe or intradermal algogen is proposed to activate nociresponsive neurons in area 3a which, via corticocortical connections, leads to the release of GABA in areas 3b/1. It is hypothesized that GABA is hyperpolarizing/inhibitory and suppresses stimulus-evoked RA neuron MFR and entrainment whenever RA neuron activity is low (as when the RF(center) stimulus is weak/near-threshold) but is depolarizing/excitatory and augments MFR and entrainment when RA neuron activity is high (when the stimulus is strong/suprathreshold).

Vibrotactile adaptation fails to enhance spatial localization in adults with autism.

A recent study [Tannan, V., Tommerdahl, M., Whitsel, B.L., 2006. Vibrotactile adaptation enhances spatial localization. Brain Res. 1102(1), 109-116 (Aug 2)] showed that pre-exposure of a skin region to a 5 s 25 Hz flutter stimulus ("adaptation") results in an approximately 2-fold improvement in the ability of neurologically healthy human adults to localize mechanical stimulation delivered to the same skin region that received the adapting stimulation. Tannan et al. [Tannan, V., Tommerdahl, M., Whitsel, B.L., 2006. Vibrotactile adaptation enhances spatial localization. Brain Res. 1102(1), 109-116 (Aug 2)] proposed that tactile spatial discriminative performance is improved following adaptation because adaptation is accompanied by an increase in the spatial contrast in the response of contralateral primary somatosensory cortex (SI) to mechanical skin stimulation--an effect identified in previous imaging studies of SI cortex in anesthetized non-human primates [e.g., Simons, S.B., Tannan, V., Chiu, J., Favorov, O.V., Whitsel, B.L., Tommerdahl, M, 2005. Amplitude-dependency of response of SI cortex to flutter stimulation. BMC Neurosci. 6(1), 43 (Jun 21) ; Tommerdahl, M., Favorov, O.V., Whitsel, B.L., 2002. Optical imaging of intrinsic signals in somatosensory cortex. Behav. Brain Res. 135, 83-91; Whitsel, B.L., Favorov, O.V., Tommerdahl, M., Diamond, M., Juliano, S., Kelly, D., 1989. Dynamic processes govern the somatosensory cortical response to natural stimulation. In: Lund, J.S., (Ed.), Sensory Processing in the Mammalian Brain. Oxford Univ. Press, New York, 79-107]. In the experiments described in this report, a paradigm identical to that employed previously by Tannan et al. [Tannan, V., Tommerdahl, M., Whitsel, B.L., 2006. Vibrotactile adaptation enhances spatial localization. Brain Res. 1102(1), 109-116 (Aug 2)] was used to study adults with autism. The results demonstrate that although cutaneous localization performance of adults with autism is significantly better than the performance of control subjects when the period of adapting stimulation is short (i.e., 0.5 s), tactile spatial discriminative capacity remained unaltered in the same subjects when the duration of adapting stimulation was increased (to 5 s). Both the failure of prior history of tactile stimulation to alter tactile spatial localization in adults with autism, and the better-than-normal tactile localization performance of adults with autism when the period of adaptation is short are concluded to be attributable to the deficient cerebral cortical GABAergic inhibitory neurotransmission characteristic of this disorder.

Duration-dependent response of SI to vibrotactile stimulation in squirrel monkey.

In previous studies, we showed that the spatial and intensive aspects of the SI response to skin flutter stimulation are modified systematically as stimulus amplitude is increased. In this study, we examined the effects of duration of skin flutter stimulation on the spatiotemporal characteristics of the response of SI cortex. Optical intrinsic signal (OIS) imaging was used to study the evoked response in SI of anesthetized squirrel monkeys to 25-Hz sinusoidal vertical skin displacement stimulation. Four stimulus durations were tested (0.5, 1.0, 2.0, and 5.0 s); all stimuli were delivered to a discrete site on the glabrous skin of the contralateral forelimb. Skin stimulation evoked a prominent increase in absorbance within the forelimb regions in SI of the contralateral hemisphere. Responses to brief (0.5 s) stimuli were weaker and spatially more extensive than responses to longer duration stimuli (1.0, 2.0, and 5.0 s). Stimuli >or=1 s in duration suppressed responses to below background levels (decreased absorbance) in regions that surrounded the maximally activated region. The magnitude of the suppression in the surrounding regions was nonuniform and usually was strongest medial and posterior to the maximally activated region. The results show that sustained (>or=1.0 s) stimulation decreases the spatial extent of the responding SI cortical population. Registration of the optical responses with the previously documented SI topographical organization strongly suggests that the cortical regions that undergo the strongest suppression represent skin sites that are normally co-stimulated during tactile exploration.

Effects of high-frequency skin stimulation on SI cortex: mechanisms and functional implications.

Optical intrinsic signal (OIS) imaging methods were used to record the responses of contralateral SI cortex to 25 Hz ("flutter") and also to 200 Hz ("vibration") stimulation of the skin. Anesthetized cats and squirrel monkeys were subjects. Separate series of experiments were carried out to evaluate the contralateral SI response to continuous, multisecond 25 Hz vs. 200 Hz stimulation (a) at multiple skin sites arranged along the proximal-distal axis of the fore- or hindlimb (Series I); (b) in the presence and absence of a ring placed in firm contact with the skin surrounding the stimulus site (Series II); (c) before and after topical application of local anesthetic to the stimulus site (Series III); and, finally, (c) to continuous 25 Hz or 200 Hz stimulation applied independently, and also concomitantly ("complex waveform stimulation") to the same skin site (Series IV). The principal findings are: (a) the relationship between the SI optical responses to 25 Hz vs. 200 Hz stimulation of a skin site varies systematically with position of the stimulus site on the limb-at a distal site both 25 Hz and 200 Hz stimulation evoke a well-maintained increase in absorbance, and as the stimulus site is shifted proximally on the limb the response to 200 Hz, but not the response to 25 Hz stimulation, converts to a frank decrease in absorbance; (b) placement of a ring about a skin site at which in the absence of a ring 200 Hz stimulation evoked a decrease in SI absorbance converts the response to 200 Hz to one consistent with increased SI RA neuronal activation (i.e., with the ring in place 200 Hz stimulation evokes a change in SI absorbance approximating the response to 25 Hz stimulation); (c) topical local anesthetic preferentially and reversibly decreases the magnitude of the absorbance increase associated with 25 Hz flutter stimulation; and (d) complex waveform stimulation consistently is associated with a smaller increase in absorbance than obtained with same-site 25 Hz stimulation. Collectively, the findings are consistent with the idea that the Pacinian (PC) afferent activity which unavoidably accompanies cutaneous flutter stimulation triggers CNS mechanisms that "funnel" (sharpen) the spatially distributed contralateral SI response to the flutter stimulus. Viewed in this context, the fact that a flutter stimulus unavoidably co-activates RA and PC afferents appears functionally beneficial because the CNS mechanisms activated by PC afferent drive modify the SI response to skin flutter in a manner predicted to enable more accurate perceptual localization than would be possible if the flutter stimulus only activated RA afferents.

Human vibrotactile frequency discriminative capacity after adaptation to 25 Hz or 200 Hz stimulation.

A two-interval forced-choice (2-IFC) tracking procedure was used to evaluate the effects of a 15-s pre-exposure to either 25 Hz or 200 Hz stimulation ("25 Hz or 200 Hz adaptation") on human vibrotactile frequency discrimination threshold (frequency DL/Weber fraction). Three subjects were studied. All stimuli (standard and comparison) were delivered to a central location on the thenar eminence of the hand. The frequency DL/Weber fraction was determined for each subject under the following conditions: (1) no recent prior exposure to vibrotactile stimulation ("unadapted"); (2) after 15 s adaptation to 25 Hz stimulation; and (3) after 15 s adaptation to 200 Hz stimulation. The results demonstrate that the effects of frequency of adaptation on frequency discriminative capacity when the standard stimulus is 25 Hz are not the same as when the standard stimulus is 200 Hz. The differential changes in the capacity of subjects to discriminate frequency of cutaneous flutter (10-50 Hz) or vibratory (>200 Hz) stimulation that occur subsequent to a 15-s exposure of the thenar to 25 Hz or 200 Hz stimulation are proposed to reflect frequency-specific, adaptation-induced modification of the response of contralateral primary somatosensory cortex (SI and SII) to skin mechanoreceptor afferent drive.

Optically recorded response of the superficial dorsal horn: dissociation from neuronal activity, sensitivity to formalin-evoked skin nociceptor activation.

In rat spinal cord, slice repetitive electrical stimulation of the dorsal root at an intensity that activates C-fibers evokes a slow-to-develop and prolonged (30-50 s) change in light transmittance (OIS(DR)) in the superficial part of the ipsilateral dorsal horn (DH(s)). Inhibition of astrocyte metabolism [by bath-applied 400 microM fluoroacetate and 200 microM glutamine (FAc + Gln)] or interference with glial and neuronal K+ transport [by 100 microM 4-aminopyridine (4-AP)] leads to dissociation of the OIS(DR) and the postsynaptic DH(s) response to a single-pulse, constant-current dorsal root stimulus (P-PSP(DR)). The OIS(DR) decreases under FAc+Gln, whereas the P-PSP(DR) remains unaltered; under 4-AP, the P-PSP(DR) increases, but the OIS(DR) decreases. In contrast, both the OIS(DR) and P-PSP(DR) increase when K(+)o is elevated to 8 mM. These observations from slices from normal subjects are interpreted to indicate that the OIS(DR) mainly reflects cell volume and light scattering changes associated with DH(s) astrocyte uptake of K+ and glutamate (GLU). In slices from subjects that received an intracutaneous injection of formalin 3-5 days earlier, both the OIS(DR) and the response of the DH(s) ipsilateral to the injection site to 100-ms local application (via puffer pipette) of 15 mM K+ or 100 microM GLU were profoundly reduced, and the normally exquisite sensitivity of the DH(s) to elevated K(+)o is decreased. Considered collectively, the observations raise the possibility that impaired regulation of DH(s) K(+)o and GLU(o) may contribute to initiation and maintenance of the CNS pain circuit and sensorimotor abnormalities that develop following intracutaneous formalin injection.

Time-dependence of SI RA neuron response to cutaneous flutter stimulation.

Spike discharge activity of RA-type SI cortical neurons was recorded extracellularly in anesthetized monkeys and cats. Multiple applications (trials) of 10-50 Hz sinusoidal vertical skin displacement stimulation ("flutter") were delivered to the receptive field (RF). Analysis revealed large and systematic temporal trends not only in SI RA neuron responsivity (measured as spikes/s and as spikes/stimulus cycle), but also in entrainment, and in phase angle of the entrained responses. In contrast to SI RA neurons, the response of RA skin afferents to comparable conditions of skin flutter stimulation exhibited little or no dynamics. The occurrence and form of the SI RA neuron response dynamics that accompany skin flutter stimulation are shown to depend on factors such as stimulus frequency and the locus of the recording site in the global cortical response pattern. Comparison of recordings obtained in near-radial vs tangential microelectrode penetrations further reveals that the SI RA neuron response dynamics that occur during skin flutter stimulation are relatively consistent within, but heterogeneous across column-sized regions. The observed SI RA neuron response dynamics are suggested to account, in part, for the improved capacity to discriminate stimulus frequency after an exposure ("adaptation") to skin flutter stimulation (Goble and Hollins, J Acoust Soc Am 96: 771-780, 1994). Parallels with recent proposals about the contributions to visual perception of short-term primary sensory cortical neuron dynamics and synchrony in multineuron spike activity patterns are identified and discussed.

Frequency-dependent response of SI RA-class neurons to vibrotactile stimulation of the receptive field.

Three 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 used optical intrinsic signal (OIS) imaging and extracellular neurophysiological recording methods together, in the same sessions, to evaluate the relationship between the SI optical and RA neuron spike train responses to low- vs high-frequency stimulation of the same skin site. RA afferent entrainment was high at all frequencies of stimulation. In contrast, SI RA neuron entrainment was much lower on average, and was strongly 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 som

Stability of rapidly adapting afferent entrainment vs responsivity.

Spike discharge activity was recorded from low-threshold, rapidly adapting, skin mechanoreceptive afferents (RA afferents) dissected from the median (forelimb) or tibial (hindlimb) nerves in anesthetized monkeys and cats. The spike activity was evoked by delivery of controlled sinusoidal vertical skin displacement ("flutter") stimuli to the receptive field (RF). The stimuli (15-30 Hz; 30-400 microm peak-to-peak amplitude; duration 0.8-15 s) were superimposed on a static skin indentation (0.5-1.0 mm) which was either maintained continuously throughout the run or applied trial-by-trial. The neural activity and the analog signal of the position of the stimulator probe were digitized at 10 kHz resolution and stored for off-line analysis. The main goal was to determine whether changes in the RA afferent response to skin flutter stimulation may be responsible for the enhanced capacity to discriminate stimulus frequency that accompanies a relatively brief (approximately 1 min) pre-exposure to such stimulation in humans. To this end, the spike train data were evaluated using methods that enabled independent measurement of entrainment and responsivity. Responsivity (response intensity) was measured as the average number of spikes/stimulus cycle, while entrainment (the degree to which evoked spike train activity is phase-locked to the stimulus) was quantitatively assessed using statistical techniques developed for the analysis of "circular" (directional) data, supplemented by methods based on the calculation of power spectra from point process data. The methods are demonstrated to enable quantification of RA afferent entrainment over a range of stimulus durations and amplitudes substantially greater than reported in previous studies. While RA afferent responsivity was found to decline to a minor extent (10-20%) both across and within stimulus trials, entrainment remained consistently high and stable, and exhibited no temporal trends or dependence on any other measured factor. The average phase angle of the entrained RA afferent response also remained stable both within and across trials, showing only a tendency to increase slightly during the initial 100-500 ms after stimulus onset. The results imply that the improved capacity to discriminate stimulus frequency that develops in response to an exposure to cutaneous flutter stimulation is not attributable to a change in RA afferent entrainment per se.

Functional neocortical microcircuitry demonstrated with intrinsic signal optical imaging in vitro.

Intrinsic signal optical imaging was used to record the changes in light transmittance evoked by electrical stimulation in slices prepared from sensorimotor cortex of young adult rats. The spatial characteristics of the optical signal evoked by stimulation of layer II/III, IV, V, or VI were clearly different. Layer IV and V stimulation elicited a radially-oriented region of increased light transmittance which was "hourglass" shaped: its tangential extent was greatest in layers II/III and layer V, and least in layer IV. Layer VI stimulation also elicited a radially-oriented signal but the tangential extent of this signal was the same across layers II-VI--that is, it was column-shaped. Upper layer stimulation produced a signal whose tangential extent was much greater in the upper layers than its radial extent to the deeper layers. The spatial form of the stimulus-evoked intrinsic signal was not dependent on the cytoarchitectonic area in which it was elicited. The tangential and radial distribution of the signal evoked by stimulation of different layers appears to reflect the connectivity of cortex, particularly the horizontal connectivity present in layers II/III, V, and VI, and the interlaminar connections that exist between layers II/III and V and from layers VI to IV. The spatial characteristics of the intrinsic signal were independent of the strength of stimulation used. The idea that inhibitory mechanisms restrict the tangential extent of the signal was evaluated in experiments in which the intrinsic signal was recorded before and after the addition of 10 microM bicuculline methiodide. In all slices studied in this way (n = 12), bicuculline methiodide drastically increased the tangential extent of the signal. In 4/12 slices, the tangential spread of the signal was asymmetric with respect to the stimulus site. Asymmetric spread of the signal occurred for both layer V and layer VI stimulation and, in 2/4 of those cases, could be attributed to a cytoarchitectonic border whose presence appeared to restrict the spread of the signal across the border. Although increasing stimulation strength did not change the spatial characteristics of the radially-oriented signal evoked by layer V or VI stimulation, at maximal stimulus intensity the signal evoked from these layers was often accompanied by a band of decreased light transmittance in the most superficial layers (layers I and II). It is concluded that in vitro intrinsic optical signal imaging allows one to image a response attributable to activation of local subsets of cortical connections. In addition, the opposite effects of high-intensity deep layer stimulation on the superficial layers vs layers III-VI of the same column raise the possibility that the most superficial layers may respond differently to repetitive input drive than the rest of the cortical column.

Responses of contralateral SI and SII in cat to same-site cutaneous flutter versus vibration.

The methods of (14)C-2-deoxyglucose ((14)C-2DG) metabolic mapping and optical intrinsic signal (OIS) imaging were used to evaluate the response evoked in the contralateral primary somatosensory receiving areas (SI and SII) of anesthetized cats by either 25 Hz ("flutter") or 200 Hz ("vibration") sinusoidal vertical skin displacement stimulation of the central pad on the distal forepaw. Unilateral 25-Hz stimulation consistently evoked a localized region of elevated (14)C-2DG uptake in both SI and SII in the contralateral hemisphere. In contrast, 200-Hz stimulation did not evoke elevated (14)C-2DG uptake in the contralateral SI but evoked a prominent, localized region of increased (14)C-2DG uptake in the contralateral SII. Experiments in which the OIS was recorded yielded results that complemented and extended the findings obtained with the 2DG method. First, 25-Hz central-pad stimulation evoked an increase in absorbance in a region in the contralateral SI and SII that corresponded closely to the region in which a similar stimulus evoked increased (14)C-2DG uptake. Second, 200-Hz stimulation of the central pad consistently evoked a substantial increase in absorbance in the contralateral SII but very little or no increase in absorbance in the contralateral SI. And third, 200-Hz central-pad stimulation usually evoked a decrease in absorbance in the same contralateral SI region that underwent an increase in absorbance during same-site 25-Hz stimulation. Experiments in which the OIS responses of both SI and SII were recorded simultaneously demonstrated that continuous (>1 s) 25-Hz central-pad stimulation evokes a prominent increase in absorbance in both SI and SII in the contralateral hemisphere, whereas only SII undergoes a sustained prominent increase in absorbance in response to 200-Hz stimulation to the same central-pad site. SI exhibits an initial, transient increase in absorbance in response to 200-Hz stimulation and at durations of stimulation >1 s, undergoes a decrease in absorbance. It was found that the stimulus-evoked absorbance changes in the contralateral SI and SII are correlated significantly during vibrotactile stimulation of the central pad-positively with 25-Hz stimulation and negatively with 200-Hz stimulation. The findings are interpreted to indicate that 25-Hz central-pad stimulation of the central pad evokes spatially localized and vigorous neuronal activation within both SI and SII in the contralateral hemisphere and that although 200-Hz stimulation evokes vigorous and well maintained neuronal activation within the contralateral SII, the principal effect on the contralateral SI of a 200-Hz stimulus lasting >1 s is inhibitory.

Response of anterior parietal cortex to cutaneous flutter versus vibration.

The response of anesthetized squirrel monkey anterior parietal (SI) cortex to 25 or 200 Hz sinusoidal vertical skin displacement stimulation was studied using the method of optical intrinsic signal (OIS) imaging. Twenty-five-Hertz ("flutter") stimulation of a discrete skin site on either the hindlimb or forelimb for 3-30 s evoked a prominent increase in absorbance within cytoarchitectonic areas 3b and 1 in the contralateral hemisphere. This response was confined to those area 3b/1 regions occupied by neurons with a receptive field (RF) that includes the stimulated skin site. In contrast, same-site 200-Hz stimulation ("vibration") for 3-30 s evoked a decrease in absorbance in a much larger territory (most frequently involving areas 3b, 1, and area 3a, but in some subjects area 2 as well) than the region that undergoes an increase in absorbance during 25-Hz flutter stimulation. The increase in absorbance evoked by 25-Hz flutter developed quickly and remained relatively constant for as long as stimulation continued (stimulus duration never exceeded 30 s). At 1-3 s after stimulus onset, the response to 200-Hz stimulation, like the response to 25-Hz flutter, consisted of a localized increase in absorbance limited to the topographically appropriate region of area 3b and/or area 1. With continuing 200-Hz stimulation, however, the early response declined, and by 4-6 s after stimulus onset, it was replaced by a prominent and spatially extensive decrease in absorbance. The spike train responses of single quickly adapting (QA) neurons were recorded extracellularly during microelectrode penetrations that traverse the optically responding regions of areas 3b and 1. Onset of either 25- or 200-Hz stimulation at a site within the cutaneous RF of a QA neuron was accompanied by a substantial increase in mean spike firing rate. With continued 200-Hz stimulation, however, QA neuron mean firing rate declined rapidly (typically within 0.5-1.0 s) to a level below that recorded at the same time after onset of same-site 25-Hz stimulation. For some neurons, the mean firing rate after the initial 0.5-1 s of an exposure to 200-Hz stimulation of the RF decreased to a level below the level of background ("spontaneous") activity. The decline in both the stimulus-evoked increases in absorbance in areas 3b/1 and spike discharge activity of area 3b/1 neurons within only a few seconds of the onset of 200-Hz skin stimulation raised the possibility that the predominant effect of continuous 200-Hz stimulation for >3 s is inhibition of area 3b/1 QA neurons. This possibility was evaluated at the neuronal population level by comparing the intrinsic signal evoked in areas 3b/1 by 25-Hz skin stimulation to the intrinsic signal evoked by a same-site skin stimulus containing both 25- and 200-Hz sinusoidal components (a "complex waveform stimulus"). Such experiments revealed that the increase in absorbance evoked in areas 3b/1 by a stimulus having both 25- and 200-Hz components was substantially smaller (especially at times >3 s after stimulus onset) than the increase in absorbance evoked by "pure" 25-Hz stimulation of the same skin site. It is concluded that within a brief time (within 1-3 s) after stimulus onset, 200-Hz skin stimulation elicits a powerful inhibitory action on area 3b/1 QA neurons. The findings appear generally consistent with the suggestion that the activity of neurons in cortical regions other than areas 3b and 1 play the leading role in the processing of high-frequency (>/=200 Hz) vibrotactile stimuli.

SI neuron response variability is stimulus tuned and NMDA receptor dependent.

Skin brushing stimuli were used to evoke spike discharge activity in single skin mechanoreceptive afferents (sMRAs) and anterior parietal cortical (SI) neurons of anesthetized monkeys (Macaca fascicularis). In the initial experiments 10-50 presentations of each of 8 different stimulus velocities were delivered to the linear skin path from which maximal spike discharge activity could be evoked. Mean rate of spike firing evoked by each velocity (MFR) was computed for the time period during which spike discharge activity exceeded background, and an across-presentations estimate of mean firing rate (MFR) was generated for each velocity. The magnitude of the trial-by-trial variation in the response (estimated as CV; where CV = standard deviation in MFR/MFR) was determined for each unit at each velocity. MFR for both sMRAs and SI neurons (MFRsMRA and MFRSI, respectively) increased monotonically with velocity over the range 1-100 cm/s. At all velocities the average estimate of intertrial response variation for SI neurons (CVSI) was substantially larger than the corresponding average for sMRAs (CVsMRA). Whereas CVsMRA increased monotonically over the range 1-100 cm/s, CVSI decreased progressively with velocity over the range 1-10 cm/s, and then increased with velocity over the range 10-100 cm/s. The position of the skin brushing stimulus in the receptive field (RF) was varied in the second series of experiments. It was found that the magnitude of CVSI varied systematically with stimulus position in the RF: that is, CVSI was lowest for a particular velocity and direction of stimulus motion when the skin brushing stimulus traversed the RF center, and CVSI increased progressively as the distance between the stimulus path and the RF center increased. In the third series of experiments, either phencylidine (PCP; 100-500 microg/kg) or ketamine (KET; 0.5-7.5 mg/kg) was administered intravenously (iv) to assess the effect of block of N-methyl-D-aspartate (NMDA) receptors on SI neuron intertrial response variation. The effects of PCP on both CVSI and MFRSI were transient, typically with full recovery occurring in 1-2 h after drug injection. The effects of KET on CVSI and MFRSI were similar to those of PCP, but were shorter in duration (15-30 min). PCP and KET administration consistently was accompanied by a reduction of CVSI. The magnitude of the reduction of CVSI by PCP or KET was associated with the magnitude of CVSI before drug administration: that is, the larger the predrug CVSI, the larger the reduction in CVSI caused by PCP or KET. PCP and KET exerted variable effects on SI neuron mean firing rate that could differ greatly from one neuron to the next. The results are interpreted to indicate that SI neuron intertrial response variation is 1) stimulus tuned (intertrial response variation is lowest when the skin stimulus moves at 10 cm/s and traverses the neuron's RF center) and 2) NMDA receptor dependent (intertrial response variation is least when NMDA receptor activity contributes minimally to the response, and increases as the contribution of NMDA receptors to the response increases).

Response of anterior parietal cortex to different modes of same-site skin stimulation.

Response of anterior parietal cortex to different modes of same-site skin stimulation. J. Neurophysiol. 80: 3272-3283, 1998. Intrinsic optical signal (IOS) imaging was used to study responses of the anterior parietal cortical hindlimb region (1 subject) and forelimb region (3 subjects) to repetitive skin stimulation. Subjects were four squirrel monkeys anesthetized with a halothane/nitrous oxide/oxygen gas mixtures. Cutaneous flutter of 25 Hz evoked a reflectance decrease in the sectors of cytoarchitectonic areas 3b and/or 1 that receive input from the stimulated skin site. The intrinsic signal evoked by 25-Hz flutter attained maximal intensity

Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode.

Temporal summation of sensory intensity was investigated in normal subjects using novel methods of thermal stimulation. A Peltier thermode was heated and then applied in a series of brief (700 ms) contacts to different sites on the glabrous skin of either hand. Repetitive contacts on the thenar or hypothenar eminence, at interstimulus intervals (ISIs) of 3 s, progressively increased the perceived intensity of a thermal sensation that followed each contact at an onset latency > 2 s. Temporal summation of these delayed (late) sensations was proportional to thermode temperature over a range of 45-53 degrees C, progressing from a nonpainful level (warmth) to painful sensations that could be rated as very strong after 10 contacts. Short-latency pain sensations rarely were evoked by such stimuli and never attained levels substantially above pain threshold for the sequences and temperatures presented. Temporal summation produced by brief contacts was greater in rate and amount than increases in sensory intensity resulting from repetitive ramping to the same temperature by a thermode in constant contact with the skin. Variation of the interval between contacts revealed a dependence of sensory intensity on interstimulus interval that is similar to physiological demonstrations of windup, where increasing frequencies of spike train activity are evoked from spinal neurons by repetitive activation of unmyelinated nociceptors. However, substantial summation at repetition rates of > or = 0.33 Hz was observed for temperatures that produced only late sensations of warmth when presented at frequencies < 0.16 Hz. Measurements of subepidermal skin temperature from anesthetized monkeys revealed different time courses for storage and dissipation of heat by the skin than for temporal summation and decay of sensory intensity for the human subjects. For example, negligible heat loss occurred during a 6-s interval between two trials of 10 contacts at 0.33 Hz, but ratings of sensory magnitude decreased from very strong levels of pain to sensations of warmth during the same interval. Evidence that temporal summation of sensory intensity during series of brief contacts relies on central integration, rather than a sensitization of peripheral receptors, was obtained using two approaches. In the first, a moderate degree of temporal summation was observed during alternating stimulation of adjacent but nonoverlapping skin sites at 0.33 Hz. Second, temporal summation was significantly attenuated by prior administration of dextromethorphan, a N-methyl-D-aspartate receptor antagonist.

Optical imaging in vitro provides evidence for the minicolumnar nature of cortical response.

The response of rat neocortical slices to electrical stimulation at the layer VI/white matter border was recorded using intrinsic signal optical imaging. The optical response of the slice is column-shaped, extends from layer VI to the pial surface, and is strongly correlated with the amplitude of simultaneously recorded evoked potentials. Spectral analysis revealed radially oriented spatial variations in the intensity of the optical signal with a period of 30-60 microm/cycle. Nissl-stained sections of slices also exhibited a radially oriented periodicity in optical density with the same period. We conclude that the periodic variations in the intrinsic optical signal correspond to stimulus-activated minicolumns.

Anterior parietal cortical response to tactile and skin-heating stimuli applied to the same skin site.

1. The response of anterior parietal cortex to skin stimuli was evaluated with optical intrinsic signal imaging and extracellular microelectrode recording methods in anesthetized squirrel monkeys. 2. Nonnoxious mechanical stimulation (vibrotactile or skin tapping) of the contralateral radial interdigital pad was accompanied by a decrease in reflectance (at 833 nm) in sectors of cytoarchitectonic areas 3b and 1. This intrinsic signal was in register with regions shown by previous receptive field mapping studies to receive low-threshold mechanoreceptor input from the radial interdigital pad. 3. A skin-heating stimulus applied to the contralateral radial interdigital pad with a stationary probe/thermode evoked no discernable intrinsic signal in areas 3b and 1, but evoked a signal within a circumscribed part of area 3a. The region of area 3a responsive to skin heating with the stationary probe/thermode was adjacent to the areas 3b and 1 regions that developed an intrinsic signal in response to vibrotactile stimulation of the same skin site. Skin heating with a stationary probe/thermode also evoked intrinsic signal in regions of areas 4 and 2 neighboring the area 3b/1 regions activated by vibrotactile stimulation of the contralateral radial interdigital pad. 4. The intrinsic signal evoked in area 3a by a series of heating stimuli to the contralateral radial interdigital pad (applied with a stationary probe/thermode) increased progressively in magnitude with repeated stimulation (exhibited slow temporal summation) and remained above prestimulus levels for a prolonged period after termination of repetitive stimulation. 5. Brief mechanical stimuli ("taps") applied to the contralateral radial interdigital pad with a probe/thermode maintained either at 37 degrees C or at 52 degrees C were accompanied by the development of an intrinsic signal in both area 3a and areas 3b/1. For the 52 degrees C stimulus, the area 3a intrinsic signal was larger and the intrinsic signal in areas 3b/1 smaller than the corresponding signals evoked by the 37 degrees C stimulus. 6. Spike discharge activity was recorded from area 3a neurons during a repetitive heating stimulus applied with a stationary probe/ thermode to the contralateral radial interdigital pad. Like the area 3a intrinsic signal elicited by repetitive heating of the same skin site, the area 3a neuron spike discharge activity also exhibited slow temporal summation and poststimulus response persistence. 7. The experimental findings suggest 1) a leading role for area 3a in the anterior parietal cortical processing of skin-heating stimuli, and 2) the presence of inhibitory interactions between the anterior parietal responses to painful and vibrotactile stimuli consistent with those demonstrated in recent cortical imaging and psychophysical studies of human subjects.

Effects of spinal dorsal column transection on the response of monkey anterior parietal cortex to repetitive skin stimulation.

The pattern of 14C-2-deoxyglucose (2DG) labeling in anterior parietal cortex was evaluated in three groups of experimental subjects: (1) subjects in which all spinal pathways projecting at short latency to the contralateral hemisphere were intact, (2) subjects with either unilateral or bilateral transection of the dorsal column pathway, and (3) subjects in whom a two-stage tractotomy (dorsal column isolation) restricted short-latency mechanoreceptor drive to that conveyed via the dorsal column pathway. Macaca fascicularis and Macaca arctoides monkeys were studied. When the spinal cord pathways projecting at short latency to contralateral anterior parietal cortex were intact, controlled vibrotactile or skin brushing stimuli evoked one or, more rarely, several loci of maximal 2DG uptake (typically 1.5-2.5 mm in diameter) in the topographically appropriate location(s) within area 3b and/or area 1. The labeling at each locus of maximal 2DG uptake extended continuously across layers II-VI. Each locus of maximal 2DG uptake was bordered on one or more sides by irregularly shaped zones of below-background 2DG uptake that could extend without interruption from area 3b into area 3a, and/or from area 1 into area 2. In the absence of skin stimulation, little or no above-background 2DG uptake occurred at any locus within areas 3b and 1 of subjects in which the dorsal column pathway on the opposite side of the spinal cord was intact. In subjects with a complete transection of the spinal dorsal column the global 2DG pattern evoked by a repetitive skin stimulus in contralateral anterior parietal cortex was a near mirror image of the pattern evoked by the same stimulus in intact subjects. In the absence of the dorsal column path, neither 10-25 Hz vibrotactile nor brushing stimulation evoked above-background uptake at the topographically appropriate location(s) within contralateral area 3b and/or area 1. Instead, a prominent region of below-background 2DG uptake occupied the topographically appropriate location in area 3b and/or area 1, and the region of suppressed 2DG uptake was bounded by one or more regions of above-background 2DG uptake that extended from areas 3b or 1 into area 3a and/or into area 2. When a two-stage spinal tractotomy prevented stimulus-evoked short-latency input from reaching contralateral anterior parietal cortex via pathways other than the dorsal column, the 2DG activity patterns evoked in contralateral cortex by either brushing or vibrotactile stimuli were similar to the patterns obtained when the somatosensory pathways on the opposite side of the spinal cord were intact. A neural network model was developed to evaluate the hypothesis that the observed cortical effects of dorsal column transection might be attributable, at least in part, to inhibitory interactions among anterior parietal cortical regions that receive their principal input from different spinal cord pathways. The model incorporated known features of (1) the cortical projection of spinal somatosensory pathways, (2) anterior parietal intrinsic and long-distance horizontal connectivity, and (3) certain neurotransmitter/receptor systems characteristic of sensory neocortex. Simulations of the model network provided results consistent with the idea that repetitive skin stimuli evoke maladaptive, time-dependent corticocortical interactions within anterior parietal cortex contralateral to a dorsal column lesion. The observations indicate that corticocortical interactions account for the (1) near mirror-image pattern (relative to the normal Mexican hat-like pattern) of anterior parietal stimulus-evoked 2DG uptake observed in subjects with a dorsal column lesion, (2) unusual time-dependent response properties of individual area 3b and 1 neurons or neuron populations deprived of dorsal column input (Dreyer et al., 1974; Vierck et al., 1990a; Makous and Vierck, 1994), and (3) abnormal time-dependent characteristics of tactile perception in monkeys with dorsal colum

Minicolumnar activation patterns in cat and monkey SI cortex.

The distribution of stimulus-evoked 14C-2-deoxyglucose (2DG) labeling in primary somatosensory cortex (SI) of monkey (Macaca fascicularis) and cat was investigated. Reconstructions of the global pattern of labeling reveal that discrete skin stimuli evoke activity within an extensive region of SI, and that the activation pattern typically consists of multiple, elongated regions of above-background labeling ("modules," typically 0.5-1.0 mm wide, and 1-4 mm long). Evidence obtained using recently developed methods (Tommerdahl, 1989) for quantitative analysis of 2DG activity patterns is shown to be consistent with the idea (Whitsel et al., 1991) that SI modules typically are bounded by zones dominated by stimulus-evoked inhibition. The labeling pattern within individual 2DG modules in SI of both cats and monkeys is analyzed quantitatively (in the frequency domain). Within-module spatial activation patterns are demonstrated to be periodic, consisting of radially oriented profiles of above-background labeling separated from each other by less strongly labeled radial profiles. The spectral characteristics of within-module 2DG labeling change systematically with location along the module's long axis: spatial frequencies between 18 and 35 cycles/mm are prominent in the labeling that occupies both the middle and upper layers at central locations in the module, but are a less obvious component of the labeling in both the middle and upper layers at locations remote to the module center. Since the radially oriented periodic variation both (1) in 2DG labeling in regions of SI outside modules and (2) in optical density in images of Nissl-stained sections of SI consists predominantly of spatial frequencies in the range of 18-35 cycles/mm, it is concluded that the radial profiles of labeling within individual 2DG modules correspond to groupings of minicolumns distinguishable from their neighbors on the basis of labeling intensity. The findings raise the possibility that highly structured, within-module spatial patterns of SI minicolumnar activation encode information about the physical properties of tactile stimuli.

The response of SI directionally selective neurons to stimulus motion occurring at two sites within the receptive field.

Data from two classes of primary somatosensory (SI) neurons (termed "direction-invariant" and "direction-variant") were analyzed to evaluate their capacity to process the directional information provided by two moving (i.e., brushing) stimuli delivered to nonoverlapping skin sites within the receptive field (RF). The stimulus sites were arranged either end to end or side by side on the skin. The two stimuli were delivered at the same time (i.e., simultaneously) or asynchronously in precisely defined orders. For both classes of neurons, and with both the end-to-end and side-by-side dual-stimulus arrangements, the response elicited by dual-site stimulation was usually much less than a linear summation of the responses elicited by independent stimulation of each site. For the direction-invariant neurons, when the two sites were arranged end to end and direction of motion at both sites was the same, directional sensitivity with dual-site stimulation most often matched or exceeded a vectorial sum of the sensitivities observed at each site when stimulated alone. In contrast, with the side-by-side arrangement, the level of directional sensitivity achieved with dual-site stimulation often failed to attain that predicted by vectorial summation of the sensitivities observed at each site. Instead, directional sensitivity under this dual-stimulus condition only approximated that attained with single-site stimulation at the more sensitive site. When noncorresponding directions of motion were presented at two sites within the RF (using either the end-to-end or side-by-side arrangement), direction-invariant neurons failed to respond differentially to opposing patterns of dual-site stimulation. For the direction-variant SI neurons, a particular end-to-end arrangement of the two sites within the RF was studied: Sites were identified on opposite sides of the within-RF boundary that in these neurons separates regions with opposite directional preferences. With this arrangement, the differential response was greater when opposite directions of motion were applied to the two sites than it was when the same direction of motion was delivered at both sites. The observations suggest that for both groups of SI neurons, the magnitude of directional sensitivity is dependent on the same attributes of dual-site stimulation that influence cutaneous directional sensitivity--that is, on the spatial arrangement of and temporal delay between the two stimuli, and on the correspondence of their directions. The effects of dual-site stimulation on the behavior of these two neuron populations appear to be in good agreement with the hypothesis that they subserve a function in tactile motion perception.