Temporal unpredictability increases error monitoring as revealed by EEG-EMG investigation.

Reacting in an unpredictable context increases error monitoring as evidenced by greater error-related negativity (ERN), an electrophysiological marker linked to an evaluation of response outcomes. We investigated whether ERN also increased when participants evaluated their responses to events that appeared in unpredictable versus predictable moments in time. We complemented electroencephalographic (EEG) analysis of cortical activity by measuring performance monitoring processes at the peripheral level using electromyography (EMG). Specifically, we used EMG data to quantify how temporal unpredictability would affect motor time (MT), the interval between the onset of muscle activity, and the mechanical response. MT increases following errors, indexing online error detection, and an attempt to stop incorrect actions. In our temporally cued version of the stop-signal task, symbolic cues predicted (temporally predictable condition) or not (temporally unpredictable condition) the onset of a target. In 25% of trials, an auditory signal occurred shortly after the target presentation, informing participants that they should inhibit their response completely. Response times were slower, and fewer inhibitory errors were made during temporally unpredictable than predictable trials, indicating enhanced control of unwanted actions when target onset time was unknown. Importantly, the ERN to inhibitory errors was greater in temporally unpredictable relative to temporally predictable conditions. Similarly, EMG data revealed prolonged MT when reactions to temporally unpredictable targets had not been stopped. Taken together, our results show that a temporally unpredictable environment increases the control of unwanted actions, both at cortical and peripheral levels, suggesting a higher subjective cost of maladaptive responses to temporally uncertain events.

Orienting attention to locations in perceptual versus mental representations.

Extensive clinical and imaging research has characterized the neural networks mediating the adaptive distribution of spatial attention. In everyday behavior, the distribution of attention is guided not only by extrapersonal targets but also by mental representations of their spatial layout. We used event-related functional magnetic resonance imaging to identify the neural system involved in directing attention to locations in arrays held as mental representations, and to compare it with the system for directing spatial attention to locations in the external world. We found that these two crucial aspects of spatial cognition are subserved by extensively overlapping networks. However, we also found that a region of right parietal cortex selectively participated in orienting attention to the extrapersonal space, whereas several frontal lobe regions selectively participated in orienting attention within on-line mental representations.

Brain activations during visual search: contributions of search efficiency versus feature binding.

We investigated the involvement of the parietal cortex in binding features during visual search using functional magnetic resonance imaging. We tested 10 subjects in four visual search tasks across which we independently manipulated (1) the requirement to integrate different types of features in a stimulus (feature or conjunction search) and (2) the degree of search efficiency (efficient or inefficient). We identified brain areas that were common to all conditions of visual search and areas that were sensitive to the factors of efficiency and feature binding. Visual search engaged an extensive network of parietal, frontal, and occipital areas. The factor of efficiency exerted a strong influence on parietal activations along the intraparietal sulcus and in the superior parietal lobule. These regions showed a main effect of efficiency and showed a simple effect when inefficient conditions were compared directly with efficient pop-out conditions in the absence of feature binding. Furthermore, a correlation analysis supported a tight correspondence between posterior parietal activation and the slope of reaction-time search functions. Conversely, feature binding during efficient pop-out search was not sufficient to modulate the parietal cortex. The results confirm the important role of the parietal cortex in visual search, but suggest that feature binding is not a requirement to engage its contribution.

The noradrenergic alpha2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting.

We examined whether the known noradrenergic attenuation of the alerting effect (the beneficial effect of a warning cue) results from an underlying effect of noradrenaline on temporal orienting (orienting toward a particular moment in time). Following a within-subjects, counterbalanced design, 10 healthy human volunteers received placebo, 200 microg clonidine or 1 mg guanfacine (alpha2 agonists) in three separate testing sessions. Subjects were scanned by fMRI while performing attentional orienting tasks containing spatially informative, temporally informative, non-informative or no cues. The alerting effect primarily activated left-lateralized prefrontal, premotor and parietal regions. Clonidine, but not guanfacine, impaired behavioural measures of the alerting effect while attenuating activity in the left temporo-parietal junction. Replicating previous results, the temporal orienting task activated left parietal and frontal cortex, while parietal cortex was activated bilaterally during spatial orienting. Of these networks, clonidine, but not guanfacine, attenuated left prefrontal cortex and insula activity during temporal orienting and attenuated right superior parietal cortex activity during spatial orienting,. To complement these neuroanatomical changes, clonidine produced selective behavioural effects on both temporal and spatial orienting. The anatomical dissociation between the effects of clonidine during temporal orienting versus alerting suggests that noradrenergic modulation of the alerting effect does not result only from an underlying effect on temporal orienting. Furthermore, we have demonstrated lateralized neuroanatomical substrates for the noradrenergic modulation of human attentional orienting in the spatial and temporal domains.

Modulation of attention by noradrenergic alpha2-agents varies according to arousal level.

The noradrenergic neurotransmitter system has been implicated in the modulation of attention by electrophysiological, behavioral and functional neuroimaging studies. Pharmacological manipulations of the alpha(2)-adrenoceptor in particular are known to modulate attentional performance in both animals and humans. This effect, however, appears to depend crucially on the underlying level of arousal of the subject being tested. For example, arousing stimuli, such as white noise, can counteract beneficial or deleterious drug effects on performance. In practice, this means that effects of alpha(2)-agonists/antagonists on behavioral or physiological indices of attention are more pronounced when general arousal is relatively low. This overall pattern of effect represents an effect of the noradrenergic alpha(2) system on the interaction between arousal and attention. Functional neuroimaging results suggest the thalamus as one of the key neuroanatomical substrates for this effect.

Orienting attention in time: behavioural and neuroanatomical distinction between exogenous and endogenous shifts.

Temporal orienting of attention is the ability to focus resources at a particular moment in time in order to optimise behaviour, and is associated with activation of left parietal and premotor cortex [Coull, J. T., Nobre, A. C. Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI. Journal of Neuroscience, 1998, 18, 7426-7435]. In the present experiment, we explored the behavioural and anatomical correlates of temporal orienting to foveal visual stimuli, in order to eliminate any spatial attention confounds. We implemented a two-way factorial design in an event-related fMRI study to examine the factors of trial validity (predictability of target by cue), length of delay (cue-target interval), and their interaction. There were two distinct types of invalid trial: those where attention was automatically drawn to a premature target and those where attention was voluntarily shifted to a delayed time-point. Reaction times for valid trials were shorter than those for invalid trials, demonstrating appropriate allocation of attention to temporal cues. All trial-types activated a shared system, including frontoparietal areas bilaterally, showing that this network is consistently associated with attentional orienting and is not specific to spatial tasks. Distinct brain areas were sensitive to cue-target delays and to trial validity. Long cue-target intervals activated areas involved in motor preparation: supplementary motor cortex, basal ganglia and thalamus. Invalid trials, where temporal expectancies were breached, showed enhanced activation of left parietal and frontal areas, and engagement of orbitofrontal cortex bilaterally. Finally, trial validity interacted with length of delay. Appearance of targets prematurely selectively activated visual extrastriate cortex; while postponement of target appearance selectively activated right prefrontal cortex. These findings suggest that distinct brain areas are involved in redirecting attention based upon sensory events (bottom-up, exogenous shifts) and based upon cognitive expectations (top-down, endogenous shifts).

Noradrenergically mediated plasticity in a human attentional neuronal network.

Noradrenaline is implicated in the modulation of attention and arousal, but the neuroanatomical basis of this effect in humans is unknown. A previous functional neuroimaging study failed to find clear effects of clonidine (alpha2 adrenoceptor agonist) on activity of brain regions implicated in attention. Therefore, we now investigate whether clonidine affects the functional integration of a neuroanatomical attentional network, by modulating connectivity between brain regions rather than activity within discrete regions. Following infusion of either clonidine or placebo, positron emission tomography measurements of brain activity were collected in 13 normal subjects while they were either resting or performing an attentional task. Effective connectivity analysis showed that during rest, clonidine decreased the functional strength of connections both from frontal cortex to thalamus and in pathways to and from visual cortex. Conversely, during the attentional task, functional integration generally increased, with changes being centered on parietal cortex (increased connectivity from locus coeruleus to parietal cortex and from parietal cortex to thalamus and frontal cortex). A drug-induced increase in the modulatory effects of frontal cortex on projections from locus coeruleus to parietal cortex was also observed. Collectively, these results highlight cognitively dissociable effects of clonidine on interactions among functionally integrated brain regions and implicate the noradrenergic system in mediating the functional integration of attentional brain systems. The context-sensitive nature of the changes are consistent with observations that noradrenergic drugs have differential effects on brain processes depending on subjects' underlying arousal levels. More generally, the results illustrate the dynamic plasticity of cognitive brain systems following neurochemical challenge.

Dissociating neuromodulatory effects of diazepam on episodic memory encoding and executive function.

RATIONALE: Diazepam and other benzodiazepines impair episodic memory encoding. Deficits in tests of executive function are also reported. In this study, we ask whether the latter effects are secondary to mnemonic impairment, or reflect specific and distinct effects of benzodiazepines on executive function. OBJECTIVES: Using positron emission tomography in healthy human volunteers, we examined similarities in the neuroanatomical correlates of the effect of diazepam on performance of executive compared to episodic memory tasks. Close similarities are proposed to reflect commonalities in the functional effects of the drug. Conversely, any evidence of task-specific regional changes in activity is proposed to reflect distinct functional effects of DZP on the two tasks. METHODS: Twelve volunteers received placebo or 10 mg diazepam in a between-subjects design. During scanning, subjects performed one of four experimental conditions, corresponding to a 2x2 factorial design, with memory encoding and executive function (on-line ordering of stimuli) as the two factors. Drug- or task-induced changes in brain activation indexed the neuroanatomical correlates of each condition. RESULTS: Averaged across all conditions, and compared to placebo, diazepam decreased activity bilaterally in prefrontal and temporal cortices. Within this network of deactivation, left dorsal prefrontal cortex activity was attenuated by diazepam during memory encoding, while left frontal opercular activity was attenuated during ordering. CONCLUSION: This neuroanatomical dissociation reflects distinct functional effects of diazepam on encoding versus ordering tasks. Therefore, the effects of diazepam on ordering tasks are not simply secondary to diazepam effects on episodic memory, but reflect real and distinct effects of the drug on executive function.

Orienting attention in time. Modulation of brain potentials.

With the aim of casting light on the neural mechanisms that support our ability to modulate visual attention over time, we recorded event-related potentials (ERPs) while normal human subjects performed a target detection task with temporal contingencies between cue and target stimuli. The task used two central cues, which predicted (80% validity) when a subsequent target would occur (either 600 or 1400 ms after cue onset). Unlike previous tasks of attentional orienting, there was no spatial information provided and all stimuli were presented foveally. Reaction times and ERPs linked to targets presented at the shorter interval showed significant effects linked to attentional orienting. Reaction times were faster when the cues correctly predicted the cue-target interval, suggesting the ability of the brain to use information about time to deploy attentional resources. ERPs differed according to the predicted time interval. In particular, the P300 amplitude and latency were enhanced when the cue predicted the cue-target interval accurately. The ERPs elicited by the cues also differed according to the time interval that they predicted. Differences were observed in potentials linked to motor preparation and expectancies. The results reveal dynamic neural activity involved in orienting attention to time intervals, as well as the consequent modulation of target-related neural activity resulting from differing temporal expectations.

The predictive value of changes in effective connectivity for human learning.

During learning, neural responses decrease over repeated exposure to identical stimuli. This repetition suppression is thought to reflect a progressive optimization of neuronal responses elicited by the task. Functional magnetic resonance imaging was used to study the neural basis of associative learning of visual objects and their locations. As expected, activation in specialized cortical areas decreased with time. However, with path analysis it was shown that, in parallel to this adaptation, increases in effective connectivity occurred between distinct cortical systems specialized for spatial and object processing. The time course of these plastic changes was highly correlated with individual learning performance, suggesting that interactions between brain areas underlie associative learning.

Monitoring for target objects: activation of right frontal and parietal cortices with increasing time on task.

The right prefrontal and parietal cortices have been implicated in attentional processing in both neuropsychological and functional neuroimaging literature. However, attention is a heterogeneous collection of processes, each of which may be underpinned by different neural networks. These attentional networks may interact, such that engaging one type of attentional process could influence the efficiency of another via overlapping neural substrates. We investigated the hypothesis that right frontal and parietal cortices provide the neuroanatomical location of the functional interaction between sustained attention and the process of selectively monitoring for target objects. Six healthy volunteers performed one of two tasks which required either selective or non-selective responding. The task lasted continuously for 18 min, during which time 3 Positron Emission Tomography (PET) scans were acquired for each task. This was repeated to obtain 12 PET measurements of regional cerebral blood flow (rCBF) for each subject. The right inferior frontal and parietal cortices were differentially activated by increasing time on task during the selective (S) vs non-selective (NS) task. Specifically, rCBF decreased with increasing time spent performing the NS task but not the S task. This result suggests that the normal deactivation in these areas as time on task increases is counteracted by the extra cognitive demands of selectively responding to target objects. Therefore, we have confirmed our hypothesis that right frontal and parietal cortices provide the neuroanatomical location for the modulation of object selection by sustained attention. We also identified the neuroanatomical correlates of each process separately, and confirmed earlier reports of prefrontal cortex and anterior cingulate activation associated with selective responding, and a fronto-parietal-thalamic network associated with sustained attention.

Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI.

Although attention is distributed across time as well as space, the temporal allocation of attention has been less well researched than its spatial counterpart. A temporal analog of the covert spatial orientation task [Posner MI, Snyder CRR, Davidson BJ (1980) Attention and the detection of signals. J Exp Psychol Gen 109:160-174] was developed to compare the neural systems involved in directing attention to spatial locations versus time intervals. We asked whether there exists a general system for allocating attentional resources, independent of stimulus dimension, or whether functionally specialized brain regions are recruited for directing attention toward spatial versus temporal aspects of the environment. We measured brain activity in seven healthy volunteers by using positron emission tomography (PET) and in eight healthy volunteers by using functional magnetic resonance imaging (fMRI). The task manipulated cued attention to spatial locations (S) and temporal intervals (T) in a factorial design. Symbolic central cues oriented subjects toward S only (left or right), toward T only (300 msec or 1500 msec), toward both S and T simultaneously, or provided no information regarding S or T. Subjects also were scanned during a resting baseline condition. Behavioral data showed benefits and costs for performance during temporal attention similar to those established for spatial attention. Brain-imaging data revealed a partial overlap between neural systems involved in the performance of spatial versus temporal orientation of attention tasks. Additionally, hemispheric asymmetries revealed preferential right and left parietal activation for spatial and temporal attention, respectively. Parietal cortex was activated bilaterally by attending to both dimensions simultaneously. This is the first direct comparison of the neural correlates of attending to spatial versus temporal cues.

Differential activation of right superior parietal cortex and intraparietal sulcus by spatial and nonspatial attention.

Neuropsychological and functional neuroimaging studies have implicated the right posterior parietal cortex (PPC) in human spatial attention. We tested the hypothesis that this area is also involved in nonspatial aspects of attention and working memory using positron emission tomography in healthy volunteers. In an initial experiment, digits were presented in pseudo-random spatial locations, and subjects attended either to locations or digits in order to detect single targets (attention condition) or to sequences of stimuli (working memory (WM) condition). Right superior parietal cortex (BA7) and intraparietal sulcus (IPS) were active during both spatial (locations) and nonspatial (digits) tasks compared to rest, although more so for the former. Additionally, right PPC was activated to an even greater extent during tests of WM than of attention, especially for tests of spatial WM. There were no differences in activation of dorsolateral prefrontal cortex in the spatial versus nonspatial versions of the task, contrary to many previous studies. A follow-up experiment which presented abstract objects in a fixed, central location confirmed that right IPS was active during tests of nonspatial attention and also that this activation is not due to incidental spatial representation of digit stimuli. However, BA7 was not activated by this nonspatial, nondigit attentional task. Overall, these data suggest first that right IPS is recruited for both nonspatial and spatial attention and WM. Second, right BA7 is recruited specifically for spatial (both direct and indirect) forms of attentional processing. Finally, PPC activations in spatial WM tasks are likely to be due to a combination of spatial perception, attention, and WM, rather than to any of these individually.

Cerebral activation in malformations of cortical development.

Malformations of cortical development (MCD) are an important aetiology of localization-related epilepsy. Previous MRI and [11C]flumazenil PET studies have demonstrated widespread structural and neuroreceptor abnormalities beyond the region of MCD that is visually apparent on MRI. We investigated the ability of brain regions affected by MCD to participate in normal cognitive and motor tasks and compared the responses seen in such patients with those in normal subjects. We studied five patients known to have MCD affecting the occipital region and seven normal subjects using H2 (15)O PET whilst they were performing a visual attention task. We also studied five right-handed patients known to have MCD affecting the left frontal lobe and seven right-handed normal subjects, using H2 (15)O PET whilst they were performing a motor learning task with the right hand. The patient and normal control data were examined using statistical parametric mapping to determine the ability of the brain region affected by MCD to participate in the task and also to detect evidence for atypical organization of cortical function in association with the MCD. Eight of the ten patients with MCD showed significant alteration of relative regional cerebral blood flow during the task compared with 'rest' in the affected brain region. These regions included focally dysgenetic cortex, the cortex lining schizencephalic clefts, heterotopic bands, subependymal grey matter heterotopia, and the cortex overlying band and subependymal heterotopia. In addition there was a significant alteration in the overall activation pattern in five patients compared with the normal control groups; in all five patients this atypical organization involved regions of cortex that appeared entirely normal on MRI. We conclude that regions of MCD may participate in normal cognitive functions but widespread cortical atypical organization may be seen. These findings have implications for surgical planning in any such patients.

Neural correlates of attention and arousal: insights from electrophysiology, functional neuroimaging and psychopharmacology.

Attention and arousal are multi-dimensional psychological processes, which interact closely with one another. The neural substrates of attention, as well as the interaction between arousal and attention, are discussed in this review. After a brief discussion of psychological and neuropsychological theories of attention, event-related potential correlates of attention are discussed. Essentially, attention acts to modulate stimulus-induced electrical potentials (N100/P100, P300, N400), rather than generating any unique potentials of its own. Functional neuroimaging studies of attentional orienting, selective attention, divided attention and sustained attention (and its inter-dependence on underlying levels of arousal) are then reviewed. A distinction is drawn between the brain areas which are crucially involved in the top-down modulation of attention (the 'sources' of attention) and those sensory-association areas whose activity is modulated by attention (the 'sites' of attentional expression). Frontal and parietal (usually right-lateralised) cortices and thalamus are most often associated with the source of attentional modulation. Also, the use of functional neuroimaging to test explicit hypotheses about psychological theories of attention is emphasised. These experimental paradigms form the basis for a 'new generation' of functional imaging studies which exploit the dynamic aspect of imaging and demonstrate how it can be used as more than just a 'brain mapping' device. Finally, a review of psychopharmacological studies in healthy human volunteers outlines the contributions of the noradrenergic, cholinergic and dopaminergic neurotransmitter systems to the neurochemical modulation of human attention and arousal. While, noradrenergic and cholinergic systems are involved in 'low-level' aspects of attention (e.g. attentional orienting), the dopaminergic system is associated with more 'executive' aspects of attention such as attentional set-shifting or working memory.

The neural correlates of the noradrenergic modulation of human attention, arousal and learning.

The prefrontal cortex has been suggested as a site of action for the noradrenergic modulation of cognition. In healthy volunteers attentional deficits can be induced by the alpha 2 adrenoceptor agonist clonidine, without impairment of more explicit tests of frontal lobe function. It is therefore possible that the effects of noradrenaline cannot be localized to a specific brain area such as the prefrontal cortex, but instead involve structures in a more widespread attentional network. A 1.5 micrograms/kg dose of clonidine or placebo was administered to 13 healthy male volunteers performing the rapid visual information processing task, which places demands on both sustained attention and working memory. Twelve positron emission tomography measurements of regional cerebral blood flow (rCBF) were collected during performance of this task and also during a rest state. A second experiment in 12 healthy volunteers examined the effects of a 1.3 micrograms/kg dose of clonidine on the rCBF changes associated with performance of a paired associates learning task compared with passive listening to word pairs. Comparison of each of the experimental tasks with its respective control replicated previous findings. A significant drug x task interaction, common to the two studies, was found in the right thalamus. Inspection of the adjusted rCBF values showed that the effect was due to attenuation of thalamic rCBF during the control states rather than to any effects of clonidine during performance of the cognitive tasks, although the effect was stronger in the rapid visual information processing study than in the paired associates learning study. The significant effect of clonidine during the control as opposed to the "cognitive' activation state is consistent with previous findings in animals and humans demonstrating greater effects of clonidine during states of relatively low arousal. The results suggest neuroanatomical dissociation of the noradrenergic modulation of arousal (via the thalamus) and attention.

A fronto-parietal network for rapid visual information processing: a PET study of sustained attention and working memory.

The rapid visual information processing (RVIP) task, a test of sustained attention which also requires working memory for its successful execution, has been used in a number of human psychopharmacological studies. Single digits are presented in quick succession (100 or 200 digits/min) on a computer screen, and target sequences of numbers must be detected with a button press. Although previous neuroimaging studies have implicated the frontal and parietal cortices in performance of simple sustained attention tasks, the neuroanatomical substrates of RVIP performance are not yet known. This information would prove invaluable in the interpretation of drug effects on this task, possibly delineating a neuronal network for neurotransmitter action. Therefore, this study investigated the functional anatomy of the RVIP task using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) in eight healthy volunteers. Subjects were required to perform variants of the RVIP task which manipulated both the level of working memory load and the speed of stimulus presentation. Compared with a rest condition (eyes closed), the RVIP task increased rCBF bilaterally in the inferior frontal gyri, parietal cortex and fusiform gyrus, and also in the right frontal superior gyrus rostrally. In comparison with a simple sustained attention control condition, the aforementioned right frontal activations were no longer apparent. We suggest that these data are consistent with the existence of a right fronto-parietal network for sustained, and possibly selective, attention, and a left fronto-parietal network for the phonological loop component of working memory.

The alpha(2) antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type.

Abstract The mixed alpha(1)/alpha(2) adrenoceptor agonist clonidine has been shown by us previously to impair certain attentional and executive functions in healthy volunteers. The present investigation examines the effects of the alpha(2) adrenoceptor antagonist idazoxan (IDZ) on cognitive function in patients with dementia of frontal type (DFT). Using a placebo-controlled ABBA design, three DFT patients were given two doses of IDZ and tested on a range of computerised tests of attention, memory and executive function. Idazoxan was found to produce dose-dependent improvements in performance, particularly on tests of planning, sustained attention, verbal fluency and episodic memory. In contrast, IDZ produced deficits in performance on a test of spatial working memory. These results suggest that IDZ may be useful as a putative cognitive enhancer, particularly in patients showing a specific pattern of frontal lobe dysfunction.