Impaired visual search in rats reveals cholinergic contributions to feature binding in visuospatial attention

The visual search task established the feature integration theory of attention in humans and measures visuospatial attentional contributions to feature binding. We recently demonstrated that the neuromodulator acetylcholine (ACh), from the nucleus basalis magnocellularis (NBM), supports the attentional processes required for feature binding using a rat digging-based task. Additional research has demonstrated cholinergic contributions from the NBM to visuospatial attention in rats. Here, we combined these lines of evidence and employed visual search in rats to examine whether cortical cholinergic input supports visuospatial attention specifically for feature binding. We trained 18 male Long-Evans rats to perform visual search using touch screen-equipped operant chambers. Sessions comprised Feature Search (no feature binding required) and Conjunctive Search (feature binding required) trials using multiple stimulus set sizes. Following acquisition of visual search, 8 rats received bilateral NBM lesions using 192 IgG-saporin to selectively reduce cholinergic afferentation of the neocortex, which we hypothesized would selectively disrupt the visuospatial attentional processes needed for efficient conjunctive visual search. As expected, relative to sham-lesioned rats, ACh-NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive Search, but not Feature Search trials, thus demonstrating that cholinergic contributions to visuospatial attention are important for feature binding in rats.     

Attentional load and sensory competition in human vision: modulation of fMRI responses by load at fixation during task-irrelevant stimulation in the peripheral visual field

Perceptual suppression of distractors may depend on both endogenous and exogenous factors, such as attentional load of the current task and sensory competition among simultaneous stimuli, respectively. We used functional magnetic resonance imaging (fMRI) to compare these two types of attentional effects and examine how they may interact in the human brain. We varied the attentional load of a visual monitoring task performed on a rapid stream at central fixation without altering the central stimuli themselves, while measuring the impact on fMRI responses to task-irrelevant peripheral checkerboards presented either unilaterally or bilaterally. Activations in visual cortex for irrelevant peripheral stimulation decreased with increasing attentional load at fixation. This relative decrease was present even in V1, but became larger for successive visual areas through to V4. Decreases in activation for contralateral peripheral checkerboards due to higher central load were more pronounced within retinotopic cortex corresponding to 'inner' peripheral locations relatively near the central targets than for more eccentric 'outer' locations, demonstrating a predominant suppression of nearby surround rather than strict 'tunnel vision' during higher task load at central fixation. Contralateral activations for peripheral stimulation in one hemifield were reduced by competition with concurrent stimulation in the other hemifield only in inferior parietal cortex, not in retinotopic areas of occipital visual cortex. In addition, central attentional load interacted with competition due to bilateral versus unilateral peripheral stimuli specifically in posterior parietal and fusiform regions. These results reveal that task-dependent attentional load, and interhemifield stimulus-competition, can produce distinct influences on the neural responses to peripheral visual stimuli within the human visual system. These distinct mechanisms in selective visual processing may be integrated within posterior parietal areas, rather than earlier occipital cortex.     

Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing

Attention-dependent modulation of neural activity in visual association cortex (VAC) is thought to depend on top-down modulatory control signals emanating from the prefrontal cortex (PFC). In a previous functional magnetic resonance imaging study utilizing a working memory task, we demonstrated that activity levels in scene-selective VAC (ssVAC) regions can be enhanced above or suppressed below a passive viewing baseline level depending on whether scene stimuli were attended or ignored (Gazzaley, Cooney, McEvoy, et al. 2005). Here, we use functional connectivity analysis to identify possible sources of these modulatory influences by examining how network interactions with VAC are influenced by attentional goals at the time of encoding. Our findings reveal a network of regions that exhibit strong positive correlations with a ssVAC seed during all task conditions, including foci in the left middle frontal gyrus (MFG). This PFC region is more correlated with the VAC seed when scenes were remembered and less correlated when scenes were ignored, relative to passive viewing. Moreover, the strength of MFG-VAC coupling correlates with the magnitude of attentional enhancement and suppression of VAC activity. Although our correlation analyses do not permit assessment of directionality, these findings suggest that PFC biases activity levels in VAC by adjusting the strength of functional coupling in accordance with stimulus relevance.     

Spatially selective representations of voluntary and stimulus-driven attentional priority in human occipital, parietal, and frontal cortex

When multiple objects are present in a visual scene, they compete for cortical processing in the visual system; selective attention biases this competition so that representations of behaviorally relevant objects enter awareness and irrelevant objects do not. Deployments of selective attention can be voluntary (e.g., shift or attention to a target's expected spatial location) or stimulus driven (e.g., capture of attention by a target-defining feature such as color). Here we use functional magnetic resonance imaging to show that both of these factors induce spatially selective attentional modulations within regions of human occipital, parietal, and frontal cortex. In addition, the voluntary attentional modulations are temporally sustained, indicating that activity in these regions dynamically tracks the locus of attention. These data show that a convolution of factors, including prior knowledge of location and target-defining features, determines the relative competitive advantage of visual stimuli within multiple stages of the visual system.     

Modulation of connectivity in visual pathways by attention: cortical interactions evaluated with structural equation modelling and fMRI

Electrophysiological and neuroimaging studies have shown that attention to visual motion can increase the responsiveness of the motion- selective cortical area V5 and the posterior parietal cortex (PP). Increased or decreased activation in a cortical area is often attributed to attentional modulation of the cortical projections to that area. This leads to the notion that attention is associated with changes in connectivity. We have addressed attentional modulation of effective connectivity using functional magnetic resonance imaging (fMRI). Three subjects were scanned under identical stimulus conditions (visual motion) while varying only the attentional component of the task. Haemodynamic responses defined an occipito-parieto-frontal network, including the, primary visual cortex (V1), V5 and PR A structural equation model of the interactions among these dorsal visual pathway areas revealed increased connectivity between V5 and PP related to attention. On the basis of our analysis and the neuroanatomical pattern of projections from the prefrontal cortex to PP we attributed the source of modulatory influences, on the posterior visual pathway, to the prefrontal cortex (PFC). To test this hypothesis we included the PFC in our model as a 'modulator' of the pathway between V5 and PP, using interaction terms in the structural equation model. This analysis revealed a significant modulatory effect of prefrontal regions on V5 afferents to posterior parietal cortex.      

Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons

The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG- saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.      

The Cerebral Cortex of the Rat and Visual Attentional Function: Dissociable Effects of Mediofrontal, Cingulate, Anterior Dorsolateral, and Parietal Cortex Lesions on a Five-Choice Serial Reaction Time Task

Dissociable effects of bilateral excitotoxic lesions of differentregions of the rat neocortex, including medial prefrontal andanterior cingulate cortices, were investigated in a five-choiceserial reaction time task that provides several indices of theaccuracy and speed of attentional function. Whereas medial prefrontalcortical lesions impaired performance of the task as revealedby a reduction in choice accuracy, an increase in the latencyto respond correctly to the visual target and enhanced perseverativeresponding, lesions of the anterior cingulate cortex specificallyincreased premature responding. By contrast, lateral frontalcortical lesions did not significantly disrupt baseline performanceof the task, but rather increased the latency to respond correctlyto the visual target during various behavioral manipulations,for example, when the length of the intertrial interval wasvaried unpredictably and during interpolation of distractingbursts of white noise. Lesions of the parietal cortex failedto disrupt any aspect of task performance investigated. These behavioral effects in the five-choice task were comparedwith the effect of these same lesions on acquisition and retentionof a one-trial passive avoidance task. The main finding fromthis paradigm was that lesions of the lateral frontal cortexproduced a significant disruption to the retention of passiveavoidance, which stands in marked contrast to the successfulretention observed by animals of the other lesion groups. Inaddition, this pattern of results reveals that the "disinhibitory"effect of cingulate cortex lesions are relatively specific tothe five-choice attentional task. Finally, the results of the present study are compared withthe findings of previous experiments using the five-choice task,which have examined the effect of selective manipulations ofthe ascending noradrenergic, cholinergic, dopaminergic. andserotonergic projections. In particular, the deficits in attentionalfunction observed following cholinergic lesions of the nucleusbasalis magnocellularis appear to be attributable to cholinergicdenervation of the medial frontal cortex. These results arediscussed in terms of the role of parallel distributed neuralsystems within the neocortex that mediate continuous attentionalperformance in the rat.     

Modulation of ventral prefrontal cortex functional connections reflects the interplay of cognitive processes and stimulus characteristics

Emerging ideas of brain function emphasize the context-dependency of regional contributions to cognitive operations, where the function of a particular region is constrained by its pattern of functional connectivity. We used functional magnetic resonance imaging to examine how modality of input (auditory or visual) affects prefrontal cortex (PFC) functional connectivity for simple working memory tasks. The hypothesis was that PFC would show contextually dependent changes in functional connectivity in relation to the modality of input despite similar cognitive demands. Participants were presented with auditory or visual bandpass-filtered noise stimuli, and performed 2 simple short-term memory tasks. Brain activation patterns independently mapped onto modality and task demands. Analysis of right ventral PFC functional connectivity, however, suggested these activity patterns interact. One functional connectivity pattern showed task differences independent of stimulus modality and involved ventromedial and dorsolateral prefrontal and occipitoparietal cortices. A second pattern showed task differences that varied with modality, engaging superior temporal and occipital association regions. Importantly, these association regions showed nonzero functional connectivity in all conditions, rather than showing a zero connectivity in one modality and nonzero in the other. These results underscore the interactive nature of brain processing, where modality-specific and process-specific networks interact for normal cognitive operations.     

Cortical substrates supporting visual search in humans.

Serial and parallel visual search tasks were presented to patients with focal lesions in dorsolateral frontal, lateral parietal, or temporal-parietal cortex. In the unilateral display conditions, search efficiency in all patient groups was similar to the normal control group for stimuli both on the ipsi- and on the contralesional side of the displays. In contrast, in the bilateral display conditions, all patient groups showed a marked delay in initiating search on the side contralateral to the lesion as compared to normal controls. This delay was more pronounced when attention demands on the ipsilateral side increased, either by making target-distractor discrimination more difficult (serial search task), or by increasing the number of ipsilateral distractor items. The contralateral deficit was evident in all patient groups, supporting the notion that dorsolateral frontal as well as posterior parietal and temporal-parietal cortex plays a critical role in visual spatial attention.     

Activation of Human Prefrontal Cortex during Spatial and Nonspatial Working Memory Tasks Measured by Functional MRI

Separate working memory domains for spatial location, and forobjects, faces, and patterns, have been identified in the prefrontalcortex (PFC) of nonhuman primates. We have used functional magneticresonance imaging to examine whether spatial and nonspatialvisual working memory processes are similarly dissociable inhuman PFC. Subjects performed tasks which required them to remembereither the location or shape of successive visual stimuli. Wefound that the mnemonic component of the working memory tasksaffected the hemispheric pattern of PFC activation. The spatial(LOCATION) working memory task preferentially activated themiddle frontal gyrus (MFG) in the right hemisphere, while thenonspatial (SHAPE) working memory task activated the NIFG inboth hemispheres. Furthermore, the area of activation in theleft hemisphere extended into the inferior frontal gyrus forthe nonspatial SHAPE task. A perceptual target (DOT) detectiontask also activated the MFG bilaterally, but at a level approximatelyhalf that of the working memory tasks. The activation in theMFG occurred within 3–6 s of task onset and declined followingtask offset. Time-course analysis revealed a different patternfor the cingulate gyrus, in which activation occurred upon taskcompletion. Cingulate activation was greatest following theSHAPE task and was greater in the left hemisphere. The presentresults support the prominent role of the PFC and, specifically,the MFG in working memory, and indicate that the mnemonic contentof the task affects the relative weighting of hemispheric activation.     

Attentional functions of parietal and frontal cortex

A model of normal attentional function, based on the concept of competitive parallel processing, is used to compare attentional deficits following parietal and frontal lobe lesions. Measurements are obtained for visual processing speed, capacity of visual short-term memory (VSTM), spatial bias (bias to left or right hemifield) and top-down control (selective attention based on task relevance). The results show important differences, but also surprising similarities, in parietal and frontal lobe patients. For processing speed and VSTM, deficits are selectively associated with parietal lesions, in particular lesions of the temporoparietal junction. We discuss explanations based on either grey matter or white matter lesions. In striking contrast, measures of attentional weighting (spatial bias and top-down control) are predicted by simple lesion volume. We suggest that attentional weights reflect competition between broadly distributed object representations. Parietal and frontal mechanisms work together, both in weighting by location and weighting by task context.     

Dissociation of stimulus relevance and saliency factors during shifts of visuospatial attention

The control of visuospatial attention entails multiple processes, including both voluntary (endogenous) factors and stimulus-driven (exogenous) factors. Exogenous processes can be triggered by visual targets presented at a previously unattended location, thus capturing attention in a stimulus-driven manner. However, little is known about the relative role of stimulus salience and behavioral relevance for this type of spatial reorienting. Here, we directly assessed how salience and relevance affect activation of the frontoparietal attentional system, using either low-salience but task-relevant target stimuli or salient but task-irrelevant flickering checkerboards. We compared event-related functional magnetic resonance imaging responses for stimuli presented at the unattended versus attended side (invalid minus valid trials), separately for the 2 categories of visual stimuli. We found that task-relevant invalid targets activated the frontoparietal attentional network, demonstrating that this system engages when target stimuli are presented at an unattended location, even when these have a low perceptual salience. Conversely, the presentation of high-salience checkerboards in one hemifield while endogenous attention was engaged elsewhere did not activate the attentional network. These findings indicate that task relevance is critical for stimulus-driven engagement of the attentional network when attentional resources are endogenously allocated somewhere else.     

Differential regulation of fronto-executive function by the monoamines and acetylcholine

The prefrontal cortex (PFC) is innervated by the monoamines, dopamine (DA), noradrenaline (NA), and serotonin, as well as acetylcholine, and the marked influence of these neurochemical systems on prefrontal working memory processes has been widely described. However, their potentially, differential contribution to prefrontal functioning is less well understood. This paper reviews evidence to support the hypothesis that these neurochemical systems recruit distinct fronto-executive operations. Direct comparison of the effects of manipulations of these neuromodulators within PFC on performance of an attentional set-shifting paradigm reveals their differential contribution to distinct task stages. Depletion of prefrontal serotonin selectively disrupts reversal learning but not attentional set formation or set shifting. In contrast, depletion of prefrontal DA disrupts set formation but not reversal learning. NA depletion on the other hand specifically impairs set-shifting, whereas its effects on reversal learning remain unclear. Finally, depletion of prefrontal acetylcholine has no effect on either set formation or set shifting but impairs serial reversal learning. Because these neurochemical systems are known to represent distinct states of stress, arousal, attention, and affect, it is postulated that they augment the different types of executive operation that are recruited and performed within these states via a synergistic interaction with the PFC.     

Face-selective neurons during passive viewing and working memory performance of rhesus monkeys: evidence for intrinsic specialization of neuronal coding.

The functional organization of prefrontal cortex (PFC) is a central issue in cognitive neuroscience. Previous physiological investigations have often failed to reveal specialization within the PFC. However, these studies have generally not been designed to examine this issue. Methodological issues such as statistical criteria for specificity, the number of neurons sampled, the extent of cortex sampled, and the number, location and nature of the stimuli used are among the variables that need to be considered in evaluating the results of studies on functional localization. In the present study, we have examined neurons in macaque monkeys trained to fixate while viewing visual stimuli, including faces, or to use them as memoranda on a working memory task. Visual responses of over 1500 neurons were recorded throughout a wide expanse of the PFC (areas 12, 9, 46, 8 and 45). Neurons were considered selective for faces if the best response to a face was over twice as strong as that to any of a wide variety of non-face stimuli. Full electrode track reconstructions in three monkeys revealed in each that neurons which met this criterion were concentrated almost exclusively in three distinct subregions within the projection region of the temporal lobe visual areas. We further show that for all neurons, the most visually selective neurons (for faces, objects or color patterns) were also the most concentrated in the temporal lobe recipient PFC. Similar face selectivity, regional specialization, and delay or delay-like activity were observed in monkeys whether trained on memory tasks or not, which suggests that these are naturally occurring properties of prefrontal neurons. These results confirm neuronal and regional specialization for information processing in PFC and elucidate how heretofore unexamined experimental variables have a strong influence on the detection of regional specialization.     

Impaired filtering of distracter stimuli by TE neurons following V4 and TEO lesions in macaques

Directing attention to a behaviorally relevant visual stimulus can overcome the distracting effects of other nearby stimuli. Correspondingly, physiological studies indicate that attention serves to filter distracting stimuli from receptive fields (RFs) in several extrastriate areas. Moreover, a recent study demonstrated that lesions of extrastriate areas V4 and TEO produce impairments in attentional filtering. A critical remaining question concerns why lesions of ventral stream areas cause attentional filtering impairments. To address this question, we tested the effects of restricted area V4 and TEO lesions on both behavioral performance and the responses of downstream neurons in area TE. The lesions impaired behavioral discrimination thresholds and altered neuronal selectivity for target stimuli in the presence of distracters. With attention to the target, but in the absence of V4 and/or TEO inputs, TE neurons responded as though attentional inputs could no longer be used to filter distracters from their RFs. This presumably occurred because top-down attentional signals were no longer able to filter distracters from the RFs of the cells that provide TE with major input. Consistent with this interpretation, increasing the spatial separation between targets and distracters, such that they no longer fell within a typical V4 RF dimension, restored both behavioral performance and neuronal selectivity in the portion of TE RFs affected by the V4 lesion.     

Flexible, capacity-limited activity of posterior parietal cortex in perceptual as well as visual short-term memory tasks

It has recently been shown, using functional magnetic resonance imaging with a change detection paradigm, that activity in posterior parietal cortex (PPC) correlates with the limited number of objects held in visual short-term memory (VSTM). We replicate this finding and extend it to tasks that use similar stimuli, but without explicit memory requirements. As well as a perceptual task used previously (detecting an item at fixation), 2 additional tasks were designed to increase attentional demands across space (searching for a red item anywhere in the array) and across both space and time (detecting a staggered offset after prolonged viewing of the array). During the VSTM task, a capacity-limited set-size effect was seen in PPC as well as occipital and frontal regions. However, the PPC showed similar activity during 2 of the tasks not requiring VSTM. These findings cannot easily be explained by behavioral performance measures or memory demands alone, suggesting a role of the PPC in processing a limited number of discrete object representations, whether in the current perceptual scene or working memory. The differential influence of item load across perceptual tasks is consistent with task requirements affecting the form of these representations.     

Control of object-based attention in human cortex

Visual attention is a mechanism by which observers select relevant or important information from the current visual array. Previous investigations have focused primarily on the ability to select a region of space for further visual analysis. These studies have revealed a distributed frontoparietal circuit that is responsible for the control of spatial attention. However, vision must ultimately represent objects and in real scenes objects often overlap spatially; thus attention must be capable of selecting objects and their properties nonspatially. Little is known about the neural basis of object-based attentional control. In two experiments, human observers shifted attention between spatially superimposed faces and houses. Event-related functional magnetic resonance imaging (fMRI) revealed attentional modulation of activity in face- and house-selective cortical regions. Posterior parietal and frontal regions were transiently active when attention was shifted between spatially superimposed perceptual objects. The timecourse of activity provides insight into the functional role that these brain regions play in attentional control processes.     

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.     

Augmented prefrontal acetylcholine release during challenged attentional performance

Previous research has demonstrated that attentional performance depends on the integrity of the cortical cholinergic input system and that such performance is associated with increases in cortical acetylcholine (ACh) release. The present experiment tested the hypothesis that the attentional impairments produced by bilateral basal forebrain infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) are associated with attenuation of performance-associated increases in ACh release. Rats were trained in a sustained attention task and equipped with three guide cannula for the bilateral infusion of the NMDA receptor antagonist APV (0, 3, 20 nmol) and for the insertion of a dialysis probe into the medial prefrontal cortex (mPFC). APV or vehicle was infused remotely following completion of the first of five blocks of trials. During the first block, attentional performance was associated with a 140% increase in ACh efflux. Infusions of APV decreased the animals' ability to detect signals and augmented the increases in ACh efflux observed prior to infusions. These data indicate a dissociation between levels of attentional performance and increases in mPFC ACh release. Augmentation of performance-associated increases in mPFC cholinergic transmission is hypothesized to mediate the increased demands on attentional 'effort' that are required to maintain performance under challenging conditions.     

Narcotic requirements for intravenous anesthesia

MAC BAR, the minimum end-tidal alveolar anesthetic concentration that inhibits adrenergic response to a noxious stimulus in 50% of subjects, is a quantifiable physiological parameter that can be used to determine potency and therapeutic indices of volatile anesthetics. We wished to determine whether there is a minimal intraarterial plasma concentration (MIC BAR) of an opiate such as fentanyl that will prevent a hypertensive response to noxious stimuli in 50% of patients undergoing aortocoronary bypass surgery (ACBP). Forty-three patients with good left ventricular function were studied. All patients were premedicated with diazepam, morphine, and scopolamine. Five groups of patients were anesthetized with different fentanyl anesthesia protocols, each designed to produce different plasma fentanyl concentrations (PFC). A 20% increase in systolic blood pressure compared to control was considered an adrenergic response that related to the plasma fentanyl concentration inferred from each patient's PFC time-concentration curve. Only four patients became hypertensive with a PFC greater than 20 ng/ml. One patient became hypertensive at intubation with a PFC of 12.3 ng/ml. There was no statistically significant difference in the mean PFC in patients who became hypertensive at each event. During aortic dissection, when significantly more patients became hypertensive, there was no difference in the incidence of hypertension in patients with a PFC above or below 20 ng/ml. Two patients became hypertensive at skin incision with a PFC over 30 ng/ml. A MIC BAR could not be identified because of the great variability in the PFC of patients who became hypertensive.(ABSTRACT TRUNCATED AT 250 WORDS)