Dynamics of history-dependent perceptual judgment.

Identical physical inputs do not always evoke identical percepts. To investigate the role of stimulus history in tactile perception, we designed a task in which rats had to judge each vibrissal vibration, in a long series, as strong or weak depending on its mean speed. After a low-speed stimulus (trial n - 1), rats were more likely to report the next stimulus (trial n) as strong, and after a high-speed stimulus, they were more likely to report the next stimulus as weak, a repulsive effect that did not depend on choice or reward on trial n - 1. This effect could be tracked over several preceding trials (i.e., n - 2 and earlier) and was characterized by an exponential decay function, reflecting a trial-by-trial incorporation of sensory history. Surprisingly, the influence of trial n - 1 strengthened as the time interval between n - 1 and n grew. Human subjects receiving fingertip vibrations showed these same key findings. We are able to account for the repulsive stimulus history effect, and its detailed time scale, through a single-parameter model, wherein each new stimulus gradually updates the subject's decision criterion. This model points to mechanisms underlying how the past affects the ongoing subjective experience.

Population coding of stimulus location in rat somatosensory cortex.

This study explores the nature of population coding in sensory cortex by applying information theoretic analyses to neuron pairs recorded simultaneously from rat barrel cortex. We quantified the roles of individual spikes and spike patterns in encoding whisker stimulus location. 82%-85% of the total information was contained in the timing of individual spikes: first spike time was particularly crucial. Spike patterns within neurons accounted for the remaining 15%-18%. Neuron pairs located in the same barrel column coded redundantly, whereas pairs in neighboring barrel columns coded independently. The barrel cortical population code for stimulus location appears to be the time of single neurons' first poststimulus spikes-a fast, robust coding mechanism that does not rely on "synergy" in crossneuronal spike patterns.

The topography of tactile working memory.

To investigate the contribution of topographically organized brain areas to tactile working memory, we asked human subjects to compare the frequency of two vibrations presented to the same fingertip or to different fingertips. The vibrations ranged from 14 to 24 Hz and were separated by a retention interval of variable length. For intervals <1 sec, subjects were accurate when both vibrations were delivered to the same fingertip but were less accurate when the two vibrations were delivered to different fingertips. For 1 or 2 sec intervals, subjects performed equally well when comparing vibrations delivered either to the same finger or to corresponding fingers on opposite hands, but they performed poorly when the vibrations were delivered to distant fingers on either hand. These results suggest that working memory resides within a topographic framework. As a further test, we performed an experiment in which the two comparison vibrations were presented to the same fingertip but an interference vibration was presented during the retention interval. The interpolated vibration disrupted accuracy most when delivered to the same finger as the comparison vibrations and had progressively less effect when delivered to more distant fingers. We conclude that topographically organized regions of somatosensory cortex contribute to tactile working memory, possibly by holding the memory trace across the retention interval. One stimulus can be accurately compared with the memory of a previous stimulus if they engage overlapping representations, but activation of the common cortical territory by an interpolated stimulus can disrupt the memory trace.

The role of spike timing in the coding of stimulus location in rat somatosensory cortex.

Although the timing of single spikes is known to code for time-varying features of a sensory stimulus, it remains unclear whether time is also exploited in the neuronal coding of the spatial structure of the environment, where nontemporal stimulus features are fundamental. This report demonstrates that, in the whisker representation of rat cortex, precise spike timing of single neurons increases the information transmitted about stimulus location by 44%, compared to that transmitted only by the total number of spikes. Crucial to this code is the timing of the first spike after whisker movement. Complex, single neuron spike patterns play a smaller, synergistic role. Timing permits very few spikes to transmit high quantities of information about a behaviorally significant, spatial stimulus.

The topography of tactile learning in humans.

The spatial distribution of learned information within a sensory system can shed light on the brain mechanisms of sensory-perceptual learning. It has been argued that tactile memories are stored within a somatotopic framework in monkeys and rats but within a widely distributed network in humans. We have performed experiments to reexamine the spread of tactile learning across the fingertips. In all experiments, subjects were trained to use one fingertip to discriminate between two stimuli. Experiment 1 required identification of vibration frequency, experiment 2 punctate pressure, and experiment 3 surface roughness. After learning to identify the stimuli reliably, subjects were tested with the trained fingertip, its first and second neighbors on the same hand, and the three corresponding fingertips on the opposite hand. As expected, for all stimulus types, subjects showed retention of learning with the trained fingertip. However, the transfer beyond the trained fingertip varied according to the stimulus type. For vibration, learning did not transfer to other fingertips. For both pressure and roughness stimuli, there was limited transfer, dictated by topographic distance; subjects performed well with the first neighbor of the trained finger and with the finger symmetrically opposite the trained one. These results indicate that tactile learning is organized within a somatotopic framework, reconciling the findings in humans with those in other species. The differential distribution of tactile memory according to stimulus type suggests that the information is stored in stimulus-specific somatosensory cortical fields, each characterized by a unique receptive field organization, feature selectivity, and callosal connectivity.

Integration of multiple-whisker inputs in rat somatosensory cortex.

Rats explore their surroundings through rhythmic movement of their mystacial vibrissae. At any given moment, multiple whiskers are simultaneously moved and may contact the surface of an object. The aim of this work is to understand how simultaneous multiple-whisker deflections are processed in the somatosensory cortex. Arrays of 25 electrodes were inserted into the vibrissal representation of barrel cortex of adult rats. Multi-unit responses were recorded during (i) stimulation of single whiskers, and (ii) simultaneous stimulation of two, three or four whiskers of a whisker arc or whisker row. The whole-array response elicited by the simultaneous stimulation of multiple-whiskers (observed response) was compared to a multiple-whisker response predictor, defined as the sum of the whole-array responses to the separate stimulation of the corresponding single whiskers. The observed response to stimulation of four whiskers was nearly always less than the predicted response, indicating a sublinear summation of multiple coincident inputs. Examining the poststimulus time course of sublinearity, we found that the earliest cortical response to whisker deflection - reflecting the thalamocortical volley - was linear, whereas the successive cortical response was highly sublinear. This suggests a cortical origin of the phenomenon.

Spatial-temporal distribution of whisker-evoked activity in rat somatosensory cortex and the coding of stimulus location.

Rats use their facial vibrissae ("whiskers") to locate and identify objects. To learn about the neural coding of contact between whiskers and objects, we investigated the representation of single-vibrissa deflection by populations of cortical neurons. Microelectrode arrays, arranged in a geometric 10 x 10 grid, were inserted into the thalamo-recipient layers of "barrel cortex" (the vibrissal region of somatosensory cortex) in urethane-anesthetized rats, and neuronal activity across large sets of barrel-columns was measured. Typically, 5 msec after deflection of a whisker a 0.2 mm(2) focus of activity emerged. It rapidly expanded, doubling in size by 7 msec, before retracting and disappearing 28-59 msec after stimulus onset. The total territory engaged by the stimulus ranged from 0.5 to 2.9 mm(2) (2-11 barrels). Stimulus site dictated the domain of activity. To quantify the coding of whisker location, we applied the population d' measure of discriminability. Activity patterns elicited by two whiskers were highly discriminable at the initial cortical response; peak discriminability typically occurred within 16 msec of stimulus onset. To determine how widely information about stimulus location was distributed, we measured population d' while excluding response data from the on-center electrodes of the two tested whiskers. Response patterns remained discriminable, indicating that information about stimulus location was distributed across barrel cortex. Taken together, these results show that single-whisker deflections are represented in a multicolumn region constrained by barrel cortex map topography. The nature of this coding allows information about stimulus location to be coded extremely rapidly and unambiguously by one to two spikes per neuron.

Ipsilateral and contralateral transfer of tactile learning.

We examined the spatial organization of perceptual learning in a cortex-dependent task. Rats learned a tactile task using four whiskers on one side of the snout, all others being clipped. These trained whiskers were then clipped and prosthetic whiskers were attached. Subsequent performance was found to be determined by the location of the prosthetic whiskers. There was partial transfer of learning to neighbouring whisker positions. In addition, there was partial transfer of learning to whisker positions on the other side of the snout, but only if the prosthetic whiskers were symmetrically opposite the trained whiskers. These findings suggest that neural changes underlying perceptual learning are distributed according to the topographic organization of the sensory cortical map.

Experience-dependent plasticity of rat barrel cortex: redistribution of activity across barrel-columns.

The redistribution of neuronal activity across rat barrel cortex following an alteration in whisker usage has been investigated. In adult rats, two mystacial vibrissae - D(2) and one neighbor, D(1) or D(3) - were left intact while all other vibrissae on that side of the snout were clipped. Neurons in contralateral barrel cortex were sampled with a microelectrode array 3.5 days later. Stimulation of clipped vibrissae produced a narrow spatial distribution of cortical activity, whereas stimulation of intact vibrissae produced a widened spatial distribution. Simultaneous recordings from multiple cortical barrel-columns suggest that changes in the effective connectivity between barrel-columns may partially account for this redistribution of sensory responses. Evidence is also presented for a second mechanism, a release from inhibition in sensory-deprived cortical areas. A model is therefore proposed where these two mechanisms operate together to regulate the cortical distribution of evoked activity.

Examination of the spatial and temporal distribution of sensory cortical activity using a 100-electrode array.

This paper introduces improved techniques for multichannel extracellular electrophysiological recordings of neurons distributed across a single layer of topographically mapped cortex. We describe the electrode array, the surgical implant techniques, and the procedures for data collection and analysis. Neural events are acquired through an array of 25 or 100 microelectrodes with a 400-microm inter-electrode spacing. One advantage of the new methodology is that implantation is achieved through transdural penetration, thereby reducing the disruption of the cortical tissue. The overall cortical territory sampled by the 25-electrode array is 1.6 x 1.6 mm (2.56 mm2) and by the 100-electrode array 3.6 x 3.6 mm (12.96 mm2). Using a recording system with 100 channels available, neural activity is simultaneously acquired on all electrodes, amplified, digitized, and stored on computer. In our data, average peak-to-peak signal/noise ratio was 11.5 and off-line waveform analysis typically allowed the separation of at least one well-discriminated single-unit per channel. The reported technique permits analysis of cortical function with high temporal and spatial resolution. We use the technique to create an 'image' of neural activity distributed across the whisker representation of rat somatosensory (barrel) cortex.

Learning through maps: functional significance of topographic organization in primary sensory cortex.

The presence of "maps" in sensory cortex is a hallmark of the mammalian nervous system, but the functional significance of topographic organization has been called into question by physiological studies claiming that patterns of neural behavioral activity transcend topographic boundaries. This paper discusses recent behavioral and physiological studies suggesting that, when animals or human subjects learn perceptual tasks, the neural modifications associated with the learning are distributed according to the spatial arrangement of the primary sensory cortical map. Topographical cortical representations of sensory events, therefore, appear to constitute a true structural framework for information processing and plasticity.

Distribution of tactile learning and its neural basis.

The brain's sensory processing systems are modified during perceptual learning. To learn more about the spatial organization of learning-related modifications, we trained rats to utilize the sensory signal from a single intact whisker to carry out a behavioral task. Once a rat had mastered the task, we clipped its "trained" whisker and attached a "prosthetic" one to a different whisker stub. We then tested the rat to determine how quickly it could relearn the task by using the new whisker. We observed that rats were immediately able to use the prosthetic whisker if it were attached to the stub of the trained whisker but not if it were attached to a different stub. Indeed, the greater the distance between the trained and prosthetic whisker, the more trials were needed to relearn the task. We hypothesized that this "transfer" of learning between whiskers might depend on how much the representations of individual whiskers overlap in primary somatosensory cortex. Testing this hypothesis by using 100-electrode cortical recordings, we found that the overlap between the cortical response patterns of two whiskers accounted well for the transfer of learning between them: The correlation between the electrophysiological and behavioral data was very high (r = 0.98). These findings suggest that a topographically distributed memory trace for sensory-perceptual learning may reside in primary sensory cortex.

Genetic evidence that EBNA-1 is needed for efficient, stable latent infection by Epstein-Barr virus.

Replication and maintenance of the 170-kb circular chromosome of Epstein-Barr virus (EBV) during latent infection are generally believed to depend upon a single viral gene product, the nuclear protein EBNA-1. EBNA-1 binds to two clusters of sites at oriP, an 1, 800-bp sequence on the EBV genome which can support replication and maintenance of artificial plasmids introduced into cell lines that contain EBNA-1. To investigate the importance of EBNA-1 to latent infection by EBV, we introduced a frameshift mutation into the EBNA-1 gene of EBV by recombination along with a flanking selectable marker. EBV genomes carrying the frameshift mutation could be isolated readily after superinfecting EBV-positive cell lines, but not if recombinant virus was used to infect EBV-negative B-cell lines or to immortalize peripheral blood B cells. EBV mutants lacking almost all of internal repeat 3, which encode a repetitive glycine and alanine domain of EBNA-1, were generated in the same way and found to immortalize B cells normally. An EBNA-1-deficient mutant of EBV was isolated and found to be incapable of establishing a latent infection of the cell line BL30 at a detectable frequency, indicating that the mutant was less than 1% as efficient as an isogenic, EBNA-1-positive strain in this assay. The data indicate that EBNA-1 is required for efficient and stable latent infection by EBV under the conditions tested. Evidence from other studies now indicates that autonomous maintenance of the EBV chromosome during latent infection does not depend on the replication initiation function of oriP. It is therefore likely that the viral chromosome maintenance (segregation) function of oriP and EBNA-1 is what is required.

CD21-Dependent infection of an epithelial cell line, 293, by Epstein-Barr virus.

Epstein-Barr virus (EBV) is invariably present in undifferentiated nasopharyngeal carcinomas, is found sporadically in other carcinomas, and replicates in the differentiated layer of the tongue epithelium in lesions of oral hairy leukoplakia. However, it is not clear how frequently or by what mechanism EBV infects epithelial cells normally. Here, we report that a human epithelial cell line, 293, can be stably infected by EBV that has been genetically marked with a selectable gene. We show that 293 cells express a relatively low level of CD21, that binding of fluorescein-labeled EBV to 293 cells can be detected, and that both the binding of virus to cells and infection can be blocked with antibodies specific for CD21. Two proteins known to form complexes with CD21 on the surface of lymphoid cells, CD35 and CD19, could not be detected at the surface of 293 cells. All infected clones of 293 cells exhibited tight latency with a pattern of gene expression similar to that of type II latency, but productive EBV replication and release of infectious virus could be induced inefficiently by forced expression of the lytic transactivators, R and Z. Low levels of mRNA specific for the transforming membrane protein of EBV, LMP-1, as well as for LMP-2, were detected; however, LMP-1 protein was either undetectable or near the limit of detection at less than 5% of the level typical of EBV-transformed B cells. A slight increase in expression of the receptor for epidermal growth factor, which can be induced in epithelial cells by LMP-1, was detected at the cell surface with two EBV-infected 293 cell clones. These results show that low levels of surface CD21 can support infection of an epithelial cell line by EBV. The results also raise the possibility that in a normal infection of epithelial cells by EBV, the LMP-1 protein is not expressed at levels that are high enough to be oncogenic and that there might be differences in the cells of EBV-associated epithelial cancers that have arisen to allow for elevated expression of LMP-1.

Computational study of experience-dependent plasticity in adult rat cortical barrel-column.

We model experience-dependent plasticity in the adult rat S1 cortical representation of the whiskers (the barrel cortex) which has been produced by trimming all whiskers on one side of the snout except two. This manipulation alters the pattern of afferent sensory activity while avoiding any direct nerve damage. Our simplified model circuitry represents multiple cortical layers and inhibitory neurons within each layer of a barrel-column. Utilizing a computational model we show that the evolution of the response bias in the barrel-column towards spared whiskers is consistent with synaptic modifications that follow the rules of the Bienenstock, Cooper and Munro (BCM) theory. The BCM theory postulates that a neuron possesses a dynamic synaptic modification threshold, thetaM, which dictates whether the neuron's activity at any given instant will lead to strengthening or weakening of the synapses impinging on it. However, the major prediction of our model is the explanation of the delay in response potentiation in the layer-IV neurons through a masking effect produced by the thresholded monotonically increasing inhibition expressed by either the logarithmic function, h(x) = mu log(1 + x), or by the power function, h(x) = mu x(0.8-0.9), where mu is a constant. Furthermore, simulated removal of the supragranular layers (layers II/III) reduces plasticity of neurons in the remaining layers (IV-VI) and points to the role of noise in synaptic plasticity.

Contribution of supragranular layers to sensory processing and plasticity in adult rat barrel cortex.

Contribution of supragranular layers to sensory processing and plasticity in adult rat barrel cortex. J. Neurophysiol. 80: 3261-3271, 1998. In mature rat primary somatic sensory cortical area (SI) barrel field cortex, the thalamic-recipient granular layer IV neurons project especially densely to layers I, II, III, and IV. A prior study showed that cells in the supragranular layers are the fastest to change their response properties to novel changes in sensory inputs. Here we examine the effect of removing supragranular circuitry on the responsiveness and synaptic plasticity of cells in the remaining layers. To remove the layer II + III (supragranular) neurons from the circuitry of barrel field cortex, N-methyl--aspartate (NMDA) was applied to the exposed dura over the barrel cortex, which destroys those neurons by excitotoxicity without detectable damage to blood vessels or axons of passage. Fifteen days after NMDA treatment, the first responsive cells encountered were 400-430 micrometers below the pial surface. In separate cases triphenyltetrazolium chloride (TTC), a vital dye taken up by living cells, was absent from the lesion area. Cytochrome oxidase (CO) activity was absent in the first few tangential sections through the barrel field in all cases before arriving at the CO-dense barrel domains. These findings indicate that the lesions were quite consistent from animal to animal. Controls consisted of applying vehicle without NMDA under similar conditions. Responses of D2 barrel cells were assessed for spontaneous activity and level of response to stimulation of the principal D2 whisker and four surround whiskers D1, D3, C2, and E2. In two additional groups of animals treated in the same way, sensory plasticity was assessed by trimming all whiskers except D2 and either D1 or D3 (called Dpaired) for 7 days before recording cortical responses. Such whisker pairing normally potentiates D2 barrel cell responses to stimulation of the two intact whiskers (D2 + Dpaired). After NMDA lesions, cortical cells still responded to all whiskers tested. Cells in lesioned cortex showed reduced response amplitude compared with sham-operated controls to all D-row whiskers. In-arc surround whisker (C2 or E2) responses were normal. Spontaneous activity did not change significantly in any remaining layer at the time tested. Modal latencies to stimulation of principal D2 or surround D1 or D3 whiskers showed no significant change after lesioning. These findings indicate that there is a reasonable preservation of the response properties of layer IV, V, VI neurons after removal of layer II-III neurons in this way. Whisker pairing plasticity in layer IV-VI D2 barrel column neurons occurred in both lesioned and sham animals but was reduced significantly in lesioned animals compared with controls. The response bias generated by whisker trimming (Dpaired/Dcut + Dpaired ratio) was less pronounced in NMDA-lesioned than sham-lesioned animals. Proportionately fewer neurons in layer IV (52 vs. 64%) and in the infragranular layers (55 vs. 68%) exhibited a clear response bias to paired whiskers. We conclude that receptive-field plasticity can occur in layers IV-VI of barrel cortex in the absence of the supragranular layer circuitry. However, layer I-III circuitry does play a role in normal receptive-field generation and is required for the full expression of whisker pairing plasticity in granular and infragranular layer cells.

Primary motor and sensory cortex activation during motor performance and motor imagery: a functional magnetic resonance imaging study.

The intensity and spatial distribution of functional activation in the left precentral and postcentral gyri during actual motor performance (MP) and mental representation [motor imagery (MI)] of self-paced finger-to-thumb opposition movements of the dominant hand were investigated in fourteen right-handed volunteers by functional magnetic resonance imaging (fMRI) techniques. Significant increases in mean normalized fMRI signal intensities over values obtained during the control (visual imagery) tasks were found in a region including the anterior bank and crown of the central sulcus, the presumed site of the primary motor cortex, during both MP (mean percentage increase, 2.1%) and MI (0.8%). In the anterior portion of the precentral gyrus and the postcentral gyrus, mean functional activity levels were also increased during both conditions (MP, 1.7 and 1.2%; MI, 0.6 and 0.4%, respectively). To locate activated foci during MI, MP, or both conditions, the time course of the signal intensities of pixels lying in the precentral or postcentral gyrus was plotted against single-step or double-step waveforms, where the steps of the waveform corresponded to different tasks. Pixels significantly (r > 0.7) activated during both MP and MI were identified in each region in the majority of subjects; percentage increases in signal intensity during MI were on average 30% as great as increases during MP. The pixels activated during both MP and MI appear to represent a large fraction of the whole population activated during MP. These results support the hypothesis that MI and MP involve overlapping neural networks in perirolandic cortical areas.

[Functional mapping of the motor and primary sensorial cortex using magnetic resonance techniques. I. Preliminary data]. / Mappa funzionale della corteccia motoria e sensoriale primaria con tecniche di Risonanza Magnetica. I. Dati preliminari.

Functional Magnetic Resonance Imaging (fMRI) techniques sensitive to the local changes in blood flow, volume and oxygenation accompanying neuronal activation are powerful tools to investigate the human brain function. Experiments were performed on 10 right-handed healthy volunteers (age range: 20-39 years), using a 1.5 T whole-body MRI system. Two oblique contiguous planes were investigated along the central sulcus of the left hemisphere. Functional images were acquired using a Gradient Echo sequence while the subjects repetitively performed sequential finger to thumb opposition movements of the right hand or mental imagery of a visual scene. Twelve images for each task were obtained over a 6-min experimental period; they were then analyzed with the software provided by the manufacturer. In all the subjects small areas were activated in both the precentral and postcentral gyrus, mean percentage signal increases during finger movement being 10.7% and 3.8%, respectively. These values are fairly higher than literature ones. However several factors, such as voxel volume, are involved in determining the measured signal increase during activation. Moreover, in most cases the software procedures provided with the MR equipment to analyze the functional images imply subjective choices. It is thus necessary to implement new software packages for the analysis of fMRI images to apply more appropriate statistical procedures and to obtain more homogeneous and objective final information.