Britta Hahn

Neuroanatomical dissociation between bottom-up and top-down processes of visuospatial selective attention.

Allocation of attentional resources to portions of the available sensory input can be regulated by bottom-up processes, i.e., spontaneous orientation towards an oncoming stimulus (stimulus-driven attention), and by top-down processes, i.e., intentionally and driven by knowledge, expectation and goals. The present study aimed at advancing the understanding of brain networks mediating bottom-up and top-down control of visuospatial attention by employing a paradigm that parametrically varied demands on these two processes. Spatial predictability of peripheral targets was parametrically varied by centrally cueing one, two, three or four of four possible locations. Reaction time decreased linearly with more precise valid cueing of the target location and increased with more precise invalid cueing. Event-related functional magnetic resonance imaging (fMRI) enabled measurement of blood oxygenation level-dependent (BOLD) responses to cues and to targets. A mostly left-hemispheric network consisting of left intraparietal sulcus, inferior and superior parietal lobule, bilateral precuneus, middle frontal gyri including superior frontal sulci, and middle occipital gyri displayed BOLD responses to cues that increased linearly with more precise spatial cueing, indicating engagement by top-down spatial selective attention. In contrast, bilateral temporoparietal junction, cingulate gyrus, right precentral gyrus and anterior and posterior insula, bilateral fusiform gyri, lingual gyri and cuneus displayed BOLD responses to targets that increased with their spatial unpredictability, indicating engagement by stimulus-driven orienting. The results suggest two largely dissociated neural networks mediating top-down and bottom-up control of visuospatial selective attention.

Nicotine Enhances Visuospatial Attention by Deactivating Areas of the Resting Brain Default Network

Nicotine-induced attentional enhancement is of potential therapeutic value. To investigate the precise attentional function(s) affected and their neuronal mechanisms, the current functional magnetic resonance imaging (fMRI) study used an attention task in which subjects responded to stimuli of high (INThigh) or low intensity presented randomly in one of four peripheral locations. Central cues of varying precision predicted the target location. In some trials, the cue was not followed by a target, allowing separate analysis of blood oxygenation level-dependent (BOLD) responses to cue. Minimally deprived smokers underwent fast event-related fMRI twice: once with a nicotine patch (21 mg) and once with a placebo patch. Matched nonsmokers were scanned twice without a patch. Behaviorally, nicotine reduced omission errors and reaction time (RT) of valid and invalid cue trials and intra-individual variability of RT and did so preferentially in trials with INThigh. The BOLD signal related to cue-only trials, regardless of cue precision, demonstrated nicotine-induced deactivation in anterior and posterior cingulate, angular gyrus, middle frontal gyrus, and cuneus. These regions overlapped with the so-called “default network,” which activates during rest and deactivates with attention-demanding activities. Partial correlations controlling for nicotine plasma levels indicated associations of deactivation by nicotine in posterior cingulate and angular gyrus with performance improvements under INThigh. Performance and regional activity in the absence of nicotine never differed between smokers and nonsmokers, ruling out a simple reversal of a deprivation-induced state. These findings suggest that nicotine improved attentional performance by downregulating resting brain function in response to task-related cues. Together with the selectivity of effects for INThigh, this suggests a nicotine-induced potentiation of the alerting properties of external stimuli.

Nicotine in an animal model of attention.

Studies in smokers have suggested that at least part of the improved psychomotor performance produced by nicotine is the result of an effect on attention. Many animal experiments have assessed the effects of nicotine and its antagonists on diverse types of learning and memory but relatively few have looked at it in tasks designed to assess attention. In a five-choice serial reaction time task (5-CSRTT), rats with restricted access to food were presented with an array of five holes; illumination of a randomly selected hole signalled that a nose-poke into it would be reinforced by food presentation. Initially, signal length and the inter-trial interval (ITI) were varied and the procedure was demonstrated to satisfy some criteria for a vigilance task. The effects of nicotine on deficits in performance induced by varying signal length and ITI were assessed. Under appropriate conditions, small doses of nicotine increased the percentage of correct responses (accuracy), decreased omission errors and reaction time, and increased anticipatory responses. Subsequently, the effects of varying the ITI were examined more extensively in a slightly modified task. Here, nicotine produced small but robust, highly significant dose-related increases in accuracy, as well as decreases in omission errors and reaction times. Nicotine also increased accuracy when light stimuli were presented in an unpredictable manner. The nicotine antagonist mecamylamine produced a modest deficit in reaction time only. It is concluded that appropriate doses of nicotine can produce robust improvements in performance of normal rats in an attentional task. The effect cannot be attributed easily to changes in sensory or motor capability, learning or memory and may provide the measures needed to investigate the neuropharmacological and neuroanatomical bases of the elusive attentional effect of nicotine.

Attentional effects of nicotinic agonists in rats.

Nicotine can increase stimulus detection, response rate and speed in the five-choice serial reaction time task, a rodent test of attention. In the present experiments, four other nicotinic agonists with different pharmacological profiles were compared in the same procedure. The response profile of epibatidine resembled that previously obtained with nicotine in that response accuracy was enhanced and omission errors and correct response latency decreased. ABT-418 transiently increased accuracy in the first 10 min of test sessions and reduced response latency. Isoarecolone caused a dose-related increase in accuracy, but had no effect on omissions or response latency. This absence of effects on response rate- or speed-related measures may be related to its previously reported reduced ability to release dopamine as compared with nicotine. The alpha7-agonist AR-R17779 was without effect on any measure, indicating that this receptor subtype may not mediate nicotinic effects on attention. Affinity constants of compounds, determined in competition binding assays targeting the alpha4beta2, alpha7, alpha3beta4 and alpha3beta2* nAChR subtypes, could not explain the differential behavioural effects observed. Differences in their functional efficacy at nAChR subtypes may instead be responsible. The finding that attentional performance and response rate and speed can be selectively modulated by nicotinic agonists is encouraging for the development of drugs with therapeutic properties similar to those of nicotine but with reduced unwanted effects.

Reduced capacity but spared precision and maintenance of working memory representations in schizophrenia

CONTEXT Working memory deficits are considered a core feature of schizophrenia. Several recent integrative articles have offered mechanistic computational and neurobiological models of the origins of this cognitive deficit. OBJECTIVE To test predictions of these models using a new experimental paradigm from the basic science literature that makes it possible to determine whether patients with schizophrenia show (1) deficits in working memory storage capacity, (2) deficits in the precision of working memory representations, and (3) an amplification of these deficits as the retention interval increases. DESIGN Case-control design. All subjects performed a color working memory test in which they were asked to recall 3 or 4 items after a 1- or 4-second delay. All subjects also received a standard measure of intelligence and the Matrics Consensus Cognitive Battery. SETTING A tertiary care research outpatient clinic. Patients A total of 31 clinically stable patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and 26 healthy volunteers participated. The 2 groups were similar in age, sex, and ethnicity distribution. MAIN OUTCOME MEASURES (1) The number of items stored in working memory and (2) the precision of the working memory representations. RESULTS Patients showed a clear reduction in the number of items stored in working memory. Patients did not differ from controls in the precision of their working memory representations. There was no evidence of delay-related amplification of impairment in either capacity or precision. CONCLUSIONS Patients do not show the type of imprecision or delay-dependent amplification of impairment that is predicted on the basis of current models of the neurobiology of schizophrenia. The models need to be revised to account for a pure reduction in the number of items that patients are able to store in working memory.

TURNING IT UPSIDE DOWN: AREAS OF PRESERVED COGNITIVE FUNCTION IN SCHIZOPHRENIA

Patients with schizophrenia demonstrate marked impairments on most clinical neuropsychological tests. These findings suggest that patients suffer from a generalized form of cognitive impairment, with little evidence of spared performance documented in several large meta-analytic reviews of the clinical literature. In contrast, we review evidence for relative sparing of aspects of attention, procedural memory, and emotional processing observed in studies that have employed experimental approaches adapted from the cognitive and affective neuroscience literature. These islands of preserved performance suggest that the cognitive deficits in schizophrenia are not as general as they appear to be when assayed with clinical neuropsychological methods. The apparent contradiction in findings across methods may offer important clues about the nature of cognitive impairment in schizophrenia. The documentation of preserved cognitive function in schizophrenia may serve to sharpen hypotheses about the biological mechanisms that are implicated in the illness.

Nicotine-induced Attentional Enhancement in Rats: Effects of Chronic Exposure to Nicotine

Consistent with human literature, previous studies identified attention-enhancing effects of nicotine in rats, using a 5-choice task. The present study addressed the influence of repeated exposure to nicotine on these effects. Over six weeks, the effects of nicotine (0.0, 0.05 and 0.2 mg/kg) given ten min before sessions were tested each week. In addition, rats were injected daily two hours after sessions. In the first week, when these post-session injections were of saline for all rats, pre-session nicotine had profound rate-disruptive effects at the larger dose. In weeks 2–6, when half the rats received post-session injections of saline and the other half of nicotine (0.4 mg/kg), the disruptive effects of pre-session nicotine had disappeared and it enhanced attentional performance on all response indices. These effects did not differ significantly between post-session treatment groups or weeks, although they appeared less pronounced in the last two weeks. When tested under modified task parameters in weeks 9 and 10, nicotine (0.1 mg/kg) robustly enhanced performance in both groups despite continuing daily post-session administration of nicotine or saline. These studies provide evidence that, following tolerance to initial disruptive effects, the nicotine-induced attentional enhancement is stable across lengthy periods of chronic exposure. This is important for potential therapeutic applications of the drug and indicates that these effects can be a continuous motive for smoking behavior.

The Relationship Between Working Memory Capacity and Broad Measures of Cognitive Ability in Healthy Adults and People With Schizophrenia

OBJECTIVE Working memory (WM) capacity, typically measured with cognitively complex span tasks, is correlated with higher order cognitive abilities in healthy adults. The goals of this study were to determine whether a more focused measure of visual WM storage capacity would show similar higher order ability correlations in healthy adults and in people with schizophrenia (PSZ), thereby demonstrating the importance of simple storage capacity; determine whether the illness alters the pattern of correlations across cognitive domains; and evaluate whether between-groups differences in WM capacity could account for the generalized cognitive impairment in PSZ. METHOD Ninety-nine PSZ and 77 healthy controls (HCs) completed a visual WM change-localization task, the Wechsler Abbreviated Scale of Intelligence (WASI), and the MATRICS Consensus Cognitive Battery (MCCB). RESULTS PSZ performed more poorly than HCs on all cognitive measures. The between-groups effect size for WM capacity was large (d = 1.11). WM robustly correlated with WASI and MCCB performance, with no significant differences in the magnitude or pattern of correlations across groups. When the groups were pooled, WM capacity correlated at r = .68 with MCCB composite score and at r = .56 with WASI estimated Full Scale IQ. WM capacity accounted for approximately 40% of the between-groups variance across the WASI and MCCB. CONCLUSIONS A simple measure of WM storage capacity is robustly associated with the higher order cognitive abilities assessed by the WASI and MCCB in HCs and PSZ. WM capacity reduction may be a critical determinant of the general cognitive impairment in PSZ.

Failure of schizophrenia patients to overcome salient distractors during working memory encoding.

BACKGROUND Prior demonstrations of impaired attentional control in schizophrenia focused on conditions in which top-down control is needed to overcome prepotent response tendencies. Attentional control over stimulus processing has received little investigation. Here, we test whether attentional control is impaired during working memory encoding when salient distractors compete with less salient task-relevant stimuli. METHODS Patients with schizophrenia (n = 28) and healthy control subjects (n = 25) performed a visuospatial working memory paradigm in which half of the to-be-encoded stimuli flickered to increase their salience. After a 2-second delay, stimuli reappeared and participants had to decide whether or not a probed item had shifted location. RESULTS In the unbiased condition where flickering and nonflickering stimuli were equally likely to be probed, both groups displayed a trend toward better memory for the flickering items. In the flicker-bias condition in which the flickering stimuli were likely to be probed, both groups displayed a robust selection advantage for the flickering items. However, in the nonflicker-bias condition in which the nonflickering stimuli were likely to be probed, only healthy control subjects showed selection of the nonflickering items. Patients displayed a trend toward preferential memory for the flickering items, as in the unbiased condition. CONCLUSIONS Both groups were able to select salient over nonsalient stimuli, but patients with schizophrenia were unable to select nonsalient over salient stimuli, consistent with impairment in the effortful control of attention. These findings demonstrate the generality of top-down control failure in schizophrenia in the face of bottom-up competition from salient stimuli as with prepotent response tendencies.

Toward the Neural Mechanisms of Reduced Working Memory Capacity in Schizophrenia

People with schizophrenia (PSZ) demonstrate reliable reductions in working memory (WM) capacity (i.e., the number of objects that can be held in memory). The present study asked whether WM impairments in PSZ can be explained by the same neural mechanisms that underlie individual differences in WM capacity among healthy individuals. Specifically, we examined event-related potentials in PSZ and healthy matched controls during a change detection task that required the storage of multiple objects in WM. The amplitude of contralateral delay activity (CDA), which correlates with WM capacity in healthy individuals, was larger in controls than in PSZ for memory loads of 3 and 5 objects, but larger in PSZ than in controls for a memory load of 1. This same pattern was found in the subgroups of PSZ and controls with an equivalent WM capacity. Moreover, the increase in CDA amplitude was correlated with individual differences in capacity in controls, but not in PSZ. These results demonstrate that WM impairment in PSZ is not associated with the same patterns of neural activity that characterize low WM capacity in healthy individuals. We propose that WM impairment in PSZ instead reflects a specific impairment in the ability to distribute attention broadly.