Neurosensory assessments of migraine.

Headache medicine is primarily dependent on patients' subjective reports of pain, which are assessed at diagnosis and throughout the duration of treatment. There is a need for an objective, quantitative biological measurement of headache pain severity. In this study, quantitative sensory testing (QST) was conducted via multi-site vibrotactile stimulation in patients with migraine. The purpose was to investigate the sensitivity of the method and to determine if the metrics obtained from migraineurs could be differentiated from controls. Metrics reflecting sensory percepts of baseline measures of stimulus amplitude discrimination, temporal order judgment, and duration discrimination were significantly different. Additional measures previously demonstrated to be sensitive to alterations in centrally-mediated information processing features such as adaptation and synchronization were also significantly different from control values. In contrast, reaction times and vibrotactile detection thresholds of migraineurs failed to differentiate them from controls, indicating that the results are not due to peripheral neuropathy or some other primary afferent mechanism. The long-term objective of the study is to develop methods that can improve diagnosis and enable more accurate assessments of treatment efficacy in migraine.

Continuous theta-burst rTMS over primary somatosensory cortex modulates tactile perception on the hand.

OBJECTIVE: Theta-burst stimulation (TBS) over the primary somatosensory cortex (SI) alters cortical excitability, and in its intermittent form (iTBS) improves tactile spatial acuity. The effects of continuous TBS (cTBS) on tactile acuity remain unknown. The present study examined the influence of cTBS over SI on temporal and spatial tactile acuity on the contralateral hand. METHODS: In separate experiments, temporal discrimination threshold (TDT) and spatial amplitude discrimination threshold (SDT) were obtained from the right hand before and for up to 34 min following real and sham cTBS (600 pulses) over left-hemisphere SI. RESULTS: CTBS reduced temporal and spatial tactile acuity for up to 18 min following real cTBS. Tactile acuity was unaltered in the groups receiving sham cTBS. CONCLUSIONS: CTBS over SI impairs both temporal and spatial domains of tactile acuity for a similar duration. SIGNIFICANCE: CTBS over SI appears to decrease neural activity within targeted cortex and has potential utility in reducing excessive sensory processing.

Rate dependency of vibrotactile stimulus modulation.

Adaptation has a pronounced impact on the perception of vibrotactile stimuli. Previously, we demonstrated that the duration of vibrotactile conditioning was directly proportional to the impact that adaptation has on sensory perception (Tannan et al., 2007b). Prior reports had proposed that the impact of adaptation on the perceived magnitude of vibrotactile stimuli was specific to the conditioning amplitude (Goble and Hollins, 1993), and this concept led us to hypothesize that if the amplitude of a vibrotactile stimulus was changed continuously, that this modulation would itself impact adaptation. In order to test this idea, two repetitive vibrotactile stimuli were simultaneously delivered to two adjacent finger tips (D2 and D3). In a matching task, a standard stimulus was maintained at constant amplitude (defined as "stationary"), while the amplitude of the test stimuli was increased at a fixed rate (i.e., 10 µm/s; defined as "non-stationary") from a null value up to the level that a subject (n=50) indicated that the two stimuli were perceived to be identical. Changing the standard amplitude yielded results consistent with Weber's Law and changing the modulation rate yielded results that were consistent with our initial hypothesis that faster modulation rates would lead to the non-stationary stimulus as being less adapted. A comparative study, using the above-described method, was conducted with 12 autism subjects who were previously reported to have below normal adaptation metrics (Tannan et al., 2008). The findings of this pilot autism study suggest that rate dependent modulation of vibrotactile stimuli could provide a more sensitive metric of adaptation, as the observations demonstrate a bimodal distribution within the autism spectrum.

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 amplitude discrimination capacity parallels magnitude changes in somatosensory cortex and follows Weber's Law.

In this study, we investigated the changes in perceptual metrics of amplitude discrimination that were observed in ten healthy human subjects with increasing intensities of stimulation. The ability to perceive differences in vibrotactile amplitude changed systematically with increasing stimulus magnitude (i.e., followed Weber's Law) in a near linear fashion (R (2) = 0.9977), and the linear fit determined by the amplitude discrimination task predicted the subjects' detection thresholds. Additionally, the perceptual metrics correlated well with observations from a previously reported study in which measures of SI cortical activity in non-human primates (squirrel monkeys) evoked by different amplitudes of vibrotactile stimulation were obtained (Simons et al. in BMC Neurosci 6:43, 2005). Stimuli were delivered simultaneously to two different skin sites (D2 and D3), enabling a method for the relatively rapid acquisition of the data. Stability and robustness of the measure, its rapid acquisition, and its apparent relationship with responses previously observed in SI cortex, led to the conclusion that deviations from the baseline values observed in the obtained perceptual metric could provide a useful indicator of cerebral cortical health.

Effects of adaptation on the capacity to differentiate simultaneously delivered dual-site vibrotactile stimuli.

The capacity of 20 healthy adult subjects for detecting differences in the amplitude of two simultaneously delivered 25 Hz vibrotactile stimuli was assessed both in the absence and presence of prior exposure to different conditions of adapting stimulation. Results obtained from this study demonstrate that increasing durations of adapting stimulation at one of the two skin sites, in the range of 0.2 to 2.0 s, lead to a systematic and progressive decrease in a subject's ability to accurately discriminate between the two different amplitudes. Delivery of adapting stimuli to both of the sites of skin stimulation prior to simultaneous delivery of the test and standard stimuli, however, leads to an improvement in amplitude discrimination performance--a finding which is consistent with prior published psychophysical studies that demonstrate improvements in discriminatory capacity with much longer durations of adaptation. Striking parallels between the results obtained in this study and those reported in a prior study of the effects of vibrotactile adaptation on the optical response of squirrel monkey contralateral SI cortex to vibrotactile stimulation [Simons, S.B., Chiu, J., Favorov, O.V., Whitsel, B.L., Tommerdahl, M., 2007. Duration-dependent response of SI to vibrotactile stimulation in squirrel monkey. J Neurophysiol. 97, 2121-9, 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, 43] suggest that the perceptual effects detected in this study could be attributable to adaptation-induced alterations of SI response.

A portable tactile sensory diagnostic device.

Current methods for applying multi-site vibratory stimuli to the skin typically involve the use of two separate vibrotactile stimulators, which can lead to difficulty with positioning of stimuli and in ensuring that stimuli are delivered perfectly in phase at the same amplitude and frequency. Previously, we reported a two-point stimulator (TPS) that was developed in order to solve the problem of delivering two-point stimuli to the skin at variable distances between the sites of stimulation. Because of the success of the TPS, we designed and fabricated a new stimulator with four significant improvements over our original device. First, the device is portable, lightweight and can be used in a variety of non-laboratory settings. Second, the device consists of two independently controlled stimulators which allow delivery of stimuli simultaneously to two distinct skin sites with different amplitude, frequency and/or phase. Third, the device automatically detects the skin surface and thus allows for much better automated control of stimulus delivery. Fourth, the device is designed for rapid manufacture and, therefore, can be made readily available to other research (non-laboratory) settings. To demonstrate the device, a modified Bekesy tracking method was used to evaluate the simultaneous amplitude discrimination capacity of 20 subjects.

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.

Stimulus-dependent effects on tactile spatial acuity.

BACKGROUND: Previous studies have shown that spatio-tactile acuity is influenced by the clarity of the cortical response in primary somatosensory cortex (SI). Stimulus characteristics such as frequency, amplitude, and location of tactile stimuli presented to the skin have been shown to have a significant effect on the response in SI. The present study observes the effect of changing stimulus parameters of 25 Hz sinusoidal vertical skin displacement stimulation ("flutter") on a human subject's ability to discriminate between two adjacent or near-adjacent skin sites. Based on results obtained from recent neurophysiological studies of the SI response to different conditions of vibrotactile stimulation, we predicted that the addition of 200 Hz vibration to the same site that a two-point flutter stimulus was delivered on the skin would improve a subject's spatio-tactile acuity over that measured with flutter alone. Additionally, similar neurophysiological studies predict that the presence of either a 25 Hz flutter or 200 Hz vibration stimulus on the unattended hand (on the opposite side of the body from the site of two-point limen testing - the condition of bilateral stimulation - which has been shown to evoke less SI cortical activity than the contralateral-only stimulus condition) would decrease a subject's ability to discriminate between two points on the skin. RESULTS: A Bekesy tracking method was employed to track a subject's ability to discriminate between two-point stimuli delivered to the skin. The distance between the two points of stimulation was varied on a trial-by-trial basis, and several different stimulus conditions were examined: (1) The "control" condition, in which 25 Hz flutter stimuli were delivered simultaneously to the two points on the skin of the attended hand, (2) the "complex" condition, in which a combination of 25 Hz flutter and 200 Hz vibration stimuli were delivered to the two points on the attended hand, and (3) a "bilateral" condition, in which 25 Hz flutter was delivered to the two points on the attended hand and a second stimulus (either flutter or vibration) was delivered to the unattended hand. The two-point limen was reduced (i.e., spatial acuity was improved) under the complex stimulus condition when compared to the control stimulus condition. Specifically, whereas adding vibration to the unilateral two-point flutter stimulus improved spatial acuity by 20 to 25%, the two-point limen was not significantly affected by substantial changes in stimulus amplitude (between 100 - 200 microm). In contrast, simultaneous stimulation of the unattended hand (contralateral to the attended site), impaired spatial acuity by 20% with flutter stimulation and by 30% with vibration stimulation. CONCLUSION: It was found that the addition of 200 Hz vibration to a two-point 25 Hz flutter stimulus significantly improved a subject's ability to discriminate between two points on the skin. Since previous studies showed that 200 Hz vibration preferentially evokes activity in cortical area SII and reduces or inhibits the spatial extent of activity in SI in the same hemisphere, the findings in this paper raise the possibility that although SI activity plays a major role in two-point discrimination on the skin, influences relayed to SI from SII in the same hemisphere may contribute importantly to SI's ability to differentially respond to stimuli applied to closely spaced skin points on the same side of the body midline.

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.

A novel device for delivering two-site vibrotactile stimuli to the skin.

Current methods for applying two-site vibration stimuli to the skin typically involve the use of two separate vibrotactile stimulators, which can lead to difficulty with positioning of stimuli and in ensuring that stimuli are delivered perfectly in phase at the same amplitude and frequency. This report describes the Two-Point Stimulator (TPS) that was developed in order to deliver two-point stimuli to the skin at variable distances between the sites of stimulation on a trial-by-trial basis. The apparatus attaches to a vibrotactile stimulator, modifying it from the standard single probe tip to two probe tips. Each of the two probe tips can be independently positioned to set the tip-to-tip spacing. Both points of the TPS are driven by the single vibrotactile stimulator and distances between the two sites can be varied on a trial-by-trial basis. To test the device, a modified Bekesy tracking method was developed and used for two-point limen testing under stimulus conditions of varying amplitude and frequency. Data collected were consistent with previously published reports, suggesting that one possible use of the device would be to provide a means for improved measures of spatio-tactile acuity.

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.

Spurious dynamics in somatosensory cortex.

Cortical networks are dynamical systems whose task is to process information. However, in addition to 'intended' dynamical behaviors, the sheer complexity of a cortical network's structure-regardless of its precise details-should generate additional 'unintended' dynamical behaviors. Dynamics observed in cortical network models and in the somatosensory cortex suggest that such spurious dynamical behaviors are likely to be pervasive but relatively simple, contributing to-rather than dominating-a network's response to stimuli. Spurious dynamics may be responsible for a variety of experimentally observed intriguing features of cortical dynamics. Because of their distributed origins and emergent nature, such dynamical features, while clearly identifiable, will resist attempts at identifying specific mechanisms to explain them. We describe some of the spurious dynamical phenomena associated with somatosensory cortical response to brushing stimulation, to illustrate how spurious dynamics can affect neurons' functional properties, cortical stimulus representation and, ultimately, perception.

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

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.