The cross-modal interaction between pain-related and saccade-related cerebral activation: a preliminary study by event-related functional magnetic resonance imaging

Pain-related cerebral activation in functional magnetic resonance imaging shows less consistent signals that decay earlier than in conventional task-related activation. This may result from pain's top-down inhibition mediated by cognitive or hemodynamic interaction that could affect activation by other modalities. Using event-related functional magnetic resonance imaging, we examined whether pain affects cerebral activation by a saccade task through such cross-modal interaction. Six right-handed volunteers underwent whole-brain echo-planar imaging on a 3.0 T magnetic resonance imaging scanner while they received thermal pain stimulus at 50 degrees C on the right forearm (P; n = 6), performed a visually guided saccade task (V; n = 6), and went through a simultaneous pain-plus-saccade paradigm (PV; n = 5). Averaged functional activation maps were synthesized and signal time courses were analyzed at activation clusters. P activated the bilateral secondary somatosensory cortex (S2). V activated the posterior, supplementary, frontal eye fields, and visual areas. PV enhanced the S2 activation and activated additional pain-related areas, including the bilateral premotor area, right insula, anterior, and posterior cingulate cortices. In contrast, V-related activation was attenuated in PV. We propose that pain caused cross-modal suppression on the oculomotor activity and that an oculomotor task enhanced pain-related activation by triggering attention toward pain. IMPLICATIONS: Pain-related cerebral activation is enhanced by attention toward pain. It may involve top-down suppression over the unrelated neural networks of saccade.     

The effects of feature attention on prestimulus cortical activity in the human visual system

Covert attention affects prestimulus activity in the visual cortex. Although most studies investigating neural mechanisms of attention have focused on the effects of spatial attention, attention can also be directed to particular features. To investigate the spatiotemporal nature of feature attention, we measured subjects' brain activity using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) while subjects attended to color or motion of a stimulus based on a visual cue, which was presented 1 s before the stimulus onset. We used the hierarchical Bayesian method that allows us to estimate cortical currents with MEG and fMRI data in the order of millimeters and milliseconds. When subjects attended to color, activity within the color-sensitive area (fusiform gyrus) was selectively enhanced within the prestimulus period. By contrast, when subjects attended to motion, activity within the motion-sensitive area (middle temporal gyrus) was selectively enhanced during this period. This effect was not seen in frontal, parietal, and lower visual areas. Additionally, this effect was transient rather than sustained, suggesting that it differs from temporal aspects of spatial attention. These results suggest that, although both spatial and feature attention modulate prestimulus activity within specific visual areas, neural mechanisms underlying these effects might be different.     

Differential contribution of right and left parietal cortex to the control of spatial attention: a simultaneous EEG-rTMS study

We have recently shown that interference with repetitive transcranial magnetic stimulation (rTMS) of right posterior intraparietal sulcus (IPS) cortex during the allocation of spatial attention leads to abnormal desynchronization of anticipatory (pretarget) electroencephalographic alpha rhythms (8-12 Hz) in occipital-parietal cortex and the detection of subsequently presented visual targets (Capotosto et al. 2009). Since lesion data suggest that lesions of the right frontoparietal cortices produce more severe and long-lasting deficits of visual spatial attention than lesions of the left hemisphere, here, we used the mentioned rTMS-electroencephalographic procedure to test if the control of anticipatory alpha rhythms by IPS is asymmetrically organized in the 2 hemispheres. Results showed that interference with either left or right IPS during covert spatial attention equally disrupted the normally lateralized anticipatory modulation of occipital visual cortex, with stronger alpha desynchronization contralaterally to the attended visual field. In contrast, only interference with right IPS induced a paradoxical pretarget synchronization of alpha rhythms and bilateral deficits of target identification. These results suggest that the control of spatial topography of anticipatory alpha rhythms in occipital-parietal cortex is shared between left and right IPS cortex, but that right IPS uniquely contributes to a bilateral prestimulus activation of occipital visual cortex.     

Directing attention to locations and to sensory modalities: multiple levels of selective processing revealed with PET

We used positron emission tomography (PET) to investigate the neural correlates of selective attention in humans. We examined the effects of attending to one side of space versus another (spatial selection) and to one sensory modality versus another (intermodal selection) during bilateral, bimodal stimulation of vision and touch. Attention toward one side resulted in greater activity in several contralateral areas. In somatosensory cortex, these spatial attentional modulations were found only when touch was relevant. In the intraparietal sulcus, spatial attentional effects were multimodal, independent of the modality attended. In occipital areas, spatial modulations were also found during both visual and tactile attention, indicating that tactile attention can affect activity in visual cortex; but occipital areas also showed more activity overall during visual attention. This suggests that while spatial attention can exert multimodal influences on visual areas, these still maintain their specificity for the visual modality. Additionally, irrespective of the attended side, attending to vision activated posterior parietal and superior premotor cortices, while attending to touch activated the parietal operculi. We conclude that attentional selection operates at multiple levels, with attention to locations and attention to modalities showing distinct effects. These jointly contribute to boost processing of stimuli at the attended location in the relevant modality.     

Cortical mechanisms of feature-based attentional control

A network of fronto-parietal cortical areas is known to be involved in the control of visual attention, but the representational scope and specific function of these areas remains unclear. Recent neuroimaging evidence has revealed the existence of both transient (attention-shift) and sustained (attention-maintenance) mechanisms of space-based and object-based attentional control. Here we investigate the neural mechanisms of feature-based attentional control in human cortex using rapid event-related functional magnetic resonance imaging (fMRI). Subjects viewed an aperture containing moving dots in which dot color and direction of motion changed once per second. At any given moment, observers attended to either motion or color. Two of six motion directions and two of six colors embedded in the stimulus stream cued subjects either to shift attention from the currently attended to the unattended feature or to maintain attention on the currently attended feature. Attentional modulation of the blood oxygenation level dependent (BOLD) fMRI signal was observed in early visual areas that are selective for motion and color. More importantly, both transient and sustained BOLD activity patterns were observed in different fronto-parietal cortical areas during shifts of attention. We suggest these differing temporal profiles reflect complementary roles in the control of attention to perceptual features.     

Parietal damage dissociates saccade planning from presaccadic perceptual facilitation

A well-known theory in the field of attention today is the premotor theory of attention which suggests that the mechanisms involved in eye movements are the same as those for spatial attention shifts. We tested a parietal damaged patient with unilateral optic ataxia and 4 controls on a dual saccade/attentional task and show a dissociation between saccadic eye movements and presaccadic perceptual enhancement at the saccade goal. Remarkably, though the patient was able to make the appropriate saccades to the left, impaired visual field (undistinguishable from saccades to his right, intact visual field), he was unable to discriminate the letter at the saccade goal (whereas his performance was like controls for letter discrimination in his right visual field). This suggests that saccade planning and presaccadic perceptual facilitation are separable--planning a saccade to a location does not necessitate that the processing of this location is enhanced. Based on these results, we suggest that the parietal cortex is necessary for the coupling between saccade planning and presaccadic perceptual facilitation.     

Oculomotor effects of delta-9-tetrahydrocannabinol in humans: implications for the functional neuroanatomy of the brain cannabinoid system

The significance of cannabinoid signaling for human cognition and motor control is still poorly understood. Here, we have investigated acute behavioral effects of oral delta-9-tetrahydrocannabinol (THC) with oculomotor paradigms in 12 healthy human subjects. Compared to baseline testing: (i) THC increased latencies of reflexive visually guided saccades, while their accuracy was not affected; (ii) latencies of memory-guided saccades were unaffected, but THC modulated accuracy of these eye movements by increasing average gain and gain variability; (iii) frequency of anticipated memory-guided saccades and antisaccade errors was increased; (iv) the saccade amplitude/peak velocity relationships were not affected. These results show that THC acts on selected aspects of saccade control, namely spatial attention shifts, fine tuning of volitional saccades, spatial working memory and inhibition of inappropriate saccades. The pattern of effects suggests modulation of neuronal activity in substantia nigra pars reticulata and/or dorsolateral prefrontal cortex and sparing of the eye fields and the final motor pathway for saccades. Behaviorally, our findings reflect the distribution of CB-1 cannabinoid receptors in the human neocortex, basal ganglia and brainstem and provide evidence for participation of the cannabinoidergic system in high level control of saccades and associated cognitive functions. Saccadic eye movements may provide an objective measure of motor and cognitive effects of cannabinoids.     

Attention-dependent suppression of metabolic activity in the early stages of the macaque visual system

In this study we used a modified double-label deoxyglucose procedure to investigate attention-dependent modulations of deoxyglucose uptake at the earliest stages of the macaque visual system. Specifically, we compared activity levels evoked during two tasks with essentially identical visual stimulation requiring different attentional demands. During a featural-attention task, the subjects had to discriminate the orientation of a grating; during a control spatial-attention task, they had to localize the position of a target point. Comparison of the resulting activity maps revealed attention-dependent changes in metabolic activity in portions of the magnocellular layers of the lateral geniculate nucleus, and the magnocellular-recipient layers 4Calpha and 4B of the striate cortex. In these early stages of the visual system, attention to the orientation of the grating suppressed the metabolic activity in a retinotopically specific band peripheral to the representation of the stimulus. These results favor an early selection model of attention. After a thalamic attention-dependent gating mechanism, irrelevant visual information outside the focus of attention may be suppressed at the level of the striate cortex, which would then result in an increased signal-to-noise ratio for the processing of the attended feature in higher-tier, less retinotopically organized, extrastriate visual areas.     

Consequences of magnocellular dysfunction on processing attended information in schizophrenia

Schizophrenia is associated with perceptual and cognitive dysfunction including impairments in visual attention. These impairments may be related to deficits in early stages of sensory/perceptual processing, particularly within the magnocellular/dorsal visual pathway. In the present study, subjects viewed high and low spatial frequency (SF) gratings designed to test functioning of the parvocellular/magnocellular pathways, respectively. Schizophrenia patients and healthy controls attended to either the low SF (magnocellularly biased) or high SF (parvocellularly biased) gratings. Functional magnetic resonance imaging (fMRI) and recordings of event-related potentials (ERPs) were carried out during task performance. Patients were impaired at detecting low-frequency targets. ERP amplitudes to low-frequency gratings were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the selection negativity), which is regarded as a neural index of feature-selective attention. Similarly, fMRI revealed that activity in extrastriate visual cortex was reduced in patients during attention to low, but not high, SF. In contrast, activity in frontal and parietal areas, previously implicated in the control of attention, did not differ between patients and controls. These findings suggest that impaired sensory processing of magnocellularly biased stimuli lead to impairments in the effective processing of attended stimuli, even when the attention control systems themselves are intact.     

The representation of spatial attention in human parietal cortex dynamically modulates with performance

The control and allocation of attention is an essential, ubiquitous neural process that gates our awareness of objects and events in the environment. Neural representations of the locus of spatial attention have been previously demonstrated in parietal cortex. However, the behavioral relevance of these neural representations is not known. While undergoing functional magnetic resonance imaging, subjects performed a covert spatial attention task that yielded a wide range of performance values. Voxels in parietal cortex selective for attended target location also dynamically modulated, becoming more or less responsive as performance levels changed. Surprisingly, this relationship was not linear. Responses peaked at intermediate performance levels and dropped both when performance was very high and when it was very low. Such dynamic modulation may represent a mechanism for organizing neural control signals according to behavioral task demands.     

Population vector analysis of primate mediodorsal thalamic activity during oculomotor delayed-response performance

To understand functional roles of the thalamic mediodorsal nucleus (MD) in sensory-to-motor information transformation during spatial working memory performance and compare with those of the dorsolateral prefrontal cortex (DLPFC), we calculated population vectors using a population of MD activities recorded during 2 tasks. In the oculomotor delayed-response (ODR) task, monkeys needed to make a memory-guided saccade to the cue location, whereas in the rotatory oculomotor delayed-response (R-ODR) task, they needed to make a memory-guided saccade 90 degrees clockwise from the cue direction. The directions of population vectors calculated from populations of cue- and response-period activities were similar to the cue and saccade target directions, respectively, which confirmed that population vectors represent information regarding the directions of the visual cue and the saccade target. We then calculated population vectors of delay-period activity using a sliding 250-ms time window. In the ODR task, population vectors were directed toward the cue direction throughout the delay. However, in the R-ODR task, they gradually rotated from the cue direction to the saccade target direction. Based on a comparison with the results obtained from DLPFC neurons, the rotation of population vectors started earlier in the MD than in the DLPFC, suggesting that the motor information regarding forthcoming saccade is provided from the MD.     

A cortico-subcortical model for generation of spatially accurate sequential saccades.

This article provides a systems framework for the analysis of cortical and subcortical interactions in the control of saccadic eye movements, A major thesis of this model is that a topography of saccade direction and amplitude is preserved through multiple projections between brain regions until they are finally transformed into a temporal pattern of activity that drives the eyes to the target. The control of voluntary saccades to visual and remembered targets is modeled in terms of interactions between posterior parietal cortex, frontal eye fields, the basal ganglia (caudate and substantia nigra), superior colliculus, mediodorsal thalamus, and the saccade generator of the brainstem. Interactions include the modulation of eye movement motor error maps by topographic inhibitory projections, dynamic remapping of spatial target representations in saccade motor error maps, and sustained neural activity that embodies spatial memory. Models of these mechanisms implemented in our Neural Simulation Language simulate behavior and neural activity described in the literature, and suggest new experiments.     

FEF TMS affects visual cortical activity

We tested whether the frontal eye field (FEF) is critical in controlling visual processing in posterior visual brain areas during the orienting of spatial attention. Short trains (5 pulses at 10 Hz) of transcranial magnetic stimulation (TMS) were applied to the right FEF during the cueing period of a covert attentional task while event-related potentials (ERPs) were simultaneously recorded from lateral posterior electrodes, where visual components are prominent. FEF TMS significantly affected the neural activity evoked by visual stimuli, as well as the ongoing neural activity recorded during earlier anticipation of the visual stimuli. The effects of FEF TMS started earlier and were greatest for brain activity recorded ipsilaterally to FEF TMS and contralaterally to the visual stimulus. The TMS-induced effect on visual ERPs occurred at the same time as ERPs were shown to be modulated by visual attention. Importantly, no similar effects were observed after TMS of a control site that was physically closer but not anatomically interconnected to the recording sites. The results show that the human FEF has a causal influence over the modulation of visual activity in posterior areas when attention is being allocated.     

Neural activity in primate parietal area 7a related to spatial analysis of visual mazes

Cognitive psychological studies of humans and monkeys solving visual mazes have provided evidence that a covert analysis of the maze takes place during periods of eye fixation interspersed between saccades, or when mazes are solved without eye movements. We investigated the neural basis of this process in posterior parietal cortex by recording the activity of single neurons in area 7a during maze solution. Monkeys were required to determine from a single point of fixation whether a critical path through the maze reached an exit or a blind ending. We found that during this process the activity of approximately one in four neurons in area 7a was spatially tuned to maze path direction. We obtained evidence that path tuning did not reflect a covert saccade plan insofar as the majority of neurons active during maze solution were not active on a delayed-saccade control task, and the minority that were active on both tasks did not exhibit congruent spatial tuning in the two conditions. We also obtained evidence that path tuning during maze solution was not due to the locations of visual receptive fields mapped outside the behavioral context of maze solution, in that receptive field centers and preferred path directions were not spatially aligned. Finally, neurons tuned to path direction were not present in area 7a when a na?ve animal viewed the same visual maze stimuli but did not solve them. These data support the hypothesis that path tuning in parietal cortex is not due to the lower level visual features of the maze stimulus, but rather is associated with maze solution, and as such, reflects a cognitive process applied to a complex visual stimulus.     

Canceling planned action: an FMRI study of countermanding saccades

We investigated the voluntary control of motor behavior by studying the process of deciding whether or not to execute a movement. We imaged the human dorsal cortex while subjects performed a countermanding task that allowed us to manipulate the probability that subjects would be able to cancel a planned saccade in response to an imperative stop signal. We modeled the behavioral data as a race between gaze-shifting mechanisms and gaze-holding mechanisms towards a finish line where a saccade is generated or canceled, and estimated that saccade cancelation took approximately 160 ms. The frontal eye fields showed greater activation on stop signal trials regardless of successful cancelation, suggesting coactivation of saccade and fixation mechanisms. The supplementary eye fields, however, distinguished between successful and unsuccessful cancelation, suggesting a role in monitoring performance. These oculomotor regions play distinct roles in the decision processes mediating saccadic choice.     

Attentional modulation of receptive field structure in area 7a of the behaving monkey

Spatial attention modulates the activity of inferior parietal neurons. A statistically rigorous approach to classical retinotopic mapping was used to quantify the receptive fields of area 7a neurons under 2 attentional conditions. Measurements were made with retinal stimulation held constant and the locus of attention manipulated covertly. Both tasks required central fixation but differed in the locus of covert attention (either on the center fixation point or on a peripheral square target in one of 25 locations). The neuron's identity over the recording session was confirmed using chaos theory to characterize unique temporal patterns. Sixty-six percent of the neurons changed prestimulus activity based on task state. Retinotopic mapping showed no evidence for foveal sparing. Attentional factors influenced visual responses for approximately 30% of the neurons. Two types of modulation were equally observed. One group of cells had a multiplicative scaling of response, with equal instances of enhancement and suppression. A second group of cells had a complex interaction of visual and attentional signals, such that spatial tuning was subject to a nonlinear modulation across the visual field based on attentional constraints. These 2 cell groups may have different roles in the shift of attention preceding motor behaviors and may underlie shifts in parietal retinotopic maps observed with intrinsic optical imaging.     

Additive effects of emotional content and spatial selective attention on electrocortical facilitation

Affectively arousing visual stimuli have been suggested to automatically attract attentional resources in order to optimize sensory processing. The present study crosses the factors of spatial selective attention and affective content, and examines the relationship between instructed (spatial) and automatic attention to affective stimuli. In addition to response times and error rate, electroencephalographic data from 129 electrodes were recorded during a covert spatial attention task. This task required silent counting of random-dot targets embedded in a 10 Hz flicker of colored pictures presented to both hemifields. Steady-state visual evoked potentials (ssVEPs) were obtained to determine amplitude and phase of electrocortical responses to pictures. An increase of ssVEP amplitude was observed as an additive function of spatial attention and emotional content. Statistical parametric mapping of this effect indicated occipito-temporal and parietal cortex activation contralateral to the attended visual hemifield in ssVEP amplitude modulation. This difference was most pronounced during selection of the left visual hemifield, at right temporal electrodes. In line with this finding, phase information revealed accelerated processing of aversive arousing, compared to affectively neutral pictures. The data suggest that affective stimulus properties modulate the spatiotemporal process along the ventral stream, encompassing amplitude amplification and timing changes of posterior and temporal cortex.     

Functional neuroanatomy of anticipatory behavior: dissociation between sensory-driven and memory-driven systems

The ability to anticipate predictable stimuli allows faster responses. The predictive saccade (PRED) task has been shown to quickly induce such anticipatory behavior in humans. In a PRED task subjects track a visual target jumping back and forth between fixed positions at a fixed time interval. During this task, saccade latencies drop from approximately 200 ms to <80 ms as subjects anticipate target appearance. This change in saccade latency indicates that subjects' behavior shifts from being sensory driven to being memory driven. We conducted functional magnetic resonance imaging studies with 10 healthy adults performing the PRED task using a standard block design. We compared the PRED task with a visually guided saccade (VGS) task using unpredictable targets matched for number, direction and amplitude of required saccades. Our results show greater activation during the PRED task in the prefrontal, pre-supplementary motor and anterior cingulate cortices, hippocampus, mediodorsal thalamus, striatum and cerebellum. The VGS task elicited greater activation in the cortical eye fields and occipital cortex. These results demonstrate the important dissociation between sensory and predictive neural control of similar saccadic eye movements. Anticipatory behavior induced by the PRED task required less sensory-related processing activity and was subserved by a distributed cortico-subcortical memory system including prefronto-striatal circuitry.     

Early Decay of Pain-related Cerebral Activation in Functional Magnetic Resonance Imaging: Comparison with Visual and Motor Tasks

Background: Although pain-related activation was localized in multiple brain areas by functional imaging, the temporal profile of its signal has been poorly understood. The authors characterized the temporal evolution of such activation in comparison to that by conventional visual and motor tasks using functional magnetic resonance imaging.

Methods: Five right-handed volunteers underwent whole brain echo-planar imaging on a 3 T magnetic resonance imaging scanner while they received pain stimulus on the right and left forearm and performed visually guided saccade and finger tapping tasks. Pain stimulus on the right and left forearm consisted of four cycles of 15-s stimulus at 47.2-49.0[degrees]C, interleaved with 30-s control at 32[degrees]C, delivered by a Peltier-type thermode, and visually guided saccade and finger tapping of three cycles of 30-s active and 30-s rest conditions. Voxel-wise t statistical maps were standardized and averaged across subjects. Blood oxygenation level-dependent signal time courses were analyzed at local maxima of representative activation clusters (t > 3.5).

Results: Pain stimulus on the right forearm activated the secondary somatosensory (S2), superior temporal, anterior cingulate, insular, prefrontal cortices, premotor area, and lenticular nucleus. Pain stimulus on the left forearm activated similar but fewer areas at less signal intensity. The S2 activation was dominant on the contralateral hemisphere. Pain-related activation was statistically weaker and showed less consistent signal time courses than visually guided saccade- and finger tapping-related activation. Pain-related signals decayed earlier before the end of stimulus, in contrast to well-sustained signal plateaus induced by visually guided saccade and finger tapping.     

Intermodal selective attention in monkeys. I: distribution and timing of effects across visual areas

This study quantified the magnitude and timing of selective attention effects across areas of the macaque visual system, including the lateral geniculate nucleus (LGN), lower cortical areas V1 and V2, and multiple higher visual areas in the dorsal and ventral processing streams. We used one stimulus configuration and behavioral paradigm, with simultaneous recordings from different areas to allow direct comparison of the distribution and timing of attention effects across the system. Streams of interdigitated auditory and visual stimuli were presented at a high rate with an irregular interstimulus interval (mean of 4/s). Attention to visual stimuli was manipulated by requiring subjects to make discriminative behavioral responses to stimuli in one sensory modality, ignoring all stimuli in the other. The attended modality was alternated across trial blocks, and difficulty of discrimination was equated across modalities. Stimulus presentation was gated, so that no stimuli were presented unless the subject gazed at the center of the visual stimulus display. Visual stimuli were diffuse light flashes differing in intensity or color and subtending 12 degrees centered at the point of gaze. Laminar event-related potential (ERP) and current source density (CSD) response profiles were sampled during multiple paired penetrations in multiple visual areas with linear array multicontact electrodes. Attention effects were assessed by comparing responses to specific visual stimuli when attended versus when visual stimuli were looked at the same way, but ignored. Effects were quantified by computing a modulation index (MI), a ratio of the differential CSD response produced by attention to the sum responses to attended and ignored visual stimuli. The average MI increased up levels of the lower visual pathways from none in the LGN to 0.0278 in V1 to 0.101 in V2 to 0.170 in V4. Above the V2 level, attention effects were larger in ventral stream areas (MI = 0. 152) than in dorsal stream areas (MI = 0.052). Although onset latencies were shortest in dorsal stream areas, attentional modulation of the early response was small relative to the stimulus-evoked response. Higher ventral stream areas showed substantial attention effects at the earliest poststimulus time points, followed by the lower visual areas V2 and V1. In all areas, attentional modulation lagged the onset of the stimulus-evoked response, and attention effects grew over the time course of the neuronal response. The most powerful, consistent, and earliest attention effects were those found to occur in area V4, during the 100-300 ms poststimulus interval. Smaller effects occurred in V2 over the same interval, and the bulk of attention effects in V1 were later. In the accompanying paper, we describe the physiology of attention effects in V1, V2 and V4.