Nicotinic receptor modulation of the default mode network.

RATIONALE: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. METHODS: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. RESULTS: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. CONCLUSIONS: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.

Load-dependent hyperdeactivation of the default mode network in people with schizophrenia.

Schizophrenia is associated with impairment in a range of cognitive functions. Neuroimaging studies have reported lower, but also higher, task-induced activation accompanying impaired performance. Differences in task-load and the ability of people with schizophrenia (PSZ) to stay engaged in the cognitive operations probed appear to underlie such discrepancies. Similarly, task-induced deactivation of the default mode network (DMN) was weaker in PSZ relative to healthy control subjects (HCS) in most studies, but some reported greater deactivation. An inability to stay engaged in the cognitive operations could account for these discrepancies, too, as it would lead to more time off-task and consequently less deactivation of DMN functions. The present study employed a change detection paradigm with small to moderate set sizes (SSs) of 1, 2, and 4 items. Task training prior to fMRI scanning abolished the group difference in no-response trials. Task-positive regions of interest (ROIs) displayed greater activation with increasing SS in both groups. PSZ showed greater activation relative to HCS at SSs 1 and 2. DMN ROIs displayed greater deactivation with increasing SS in PSZ, but not in HCS, and PSZ tended to hyperdeactivate DMN regions at SS 4. No hypodeactivation was observed in PSZ. In conclusion, when minimizing differences in task-engagement, PSZ tend to over-recruit task-positive regions during low-load operations, and hyperdeactivate DMN functions at higher load, perhaps reflecting heightened non-specific vigilance or effort when dealing with cognitive challenges. This speaks against an inability to down-regulate task-independent thought processes as a primary mechanism underlying cognitive impairment in schizophrenia.

Hyperdeactivation of the Default Mode Network in People With Schizophrenia When Focusing Attention in Space.

When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits than healthy control subjects (HCS) by cues that predicts the location of a target stimulus relative to non-predictive cues. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue is non-predictive. Over-recruitment of regions involved in top-down focusing of spatial attention in response to predictive cues would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the dorsal attention network while PSZ (N = 20) and HCS (N = 20) performed a visuospatial attention task. A central cue either predicted at which of 4 peripheral locations a target signal would appear, or it gave no information about the target location. As observed previously, PSZ displayed a larger reaction time difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than non-predictive cues. This effect was almost identical between PSZ and HCS. There was no sign of over-recruitment when the cue was predictive, or of inappropriate recruitment when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network. Unexpectedly, PSZ displayed significantly greater deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space.

A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia.

BACKGROUND: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. METHODS: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. RESULTS: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. CONCLUSIONS: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts.

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.

Kraepelin and Bleuler had it right: people with schizophrenia have deficits sustaining attention over time.

An inability to sustain attention was noted in the original clinical descriptions of schizophrenia, but the vast majority of experimental studies have failed to report a performance decrement over time, calling this observation into question. To test for such deficits when task conditions conform to basic science taxonomy for the validity of sustained attention tasks, a dynamic stimulus array was presented in which targets, differing subtly from standard stimuli, were presented infrequently and unpredictably. Both people with schizophrenia (PSZ, n=40) and healthy control subjects (HCS, n=29) displayed a reduction in hit rate and an increase in reaction time (RT) from the first to the second 5-min period. Thereafter, the hit rate of HCS recovered and remained stable, while that of PSZ continued to decline. When performance at task onset was equated between groups, the decrement over time in PSZ remained of the same robust magnitude. Thus, when the nature of the task challenges sustaining attention over time, PSZ display a clear deficit in this ability.

Visuospatial attention in schizophrenia: deficits in broad monitoring.

Although selective attention is thought to be impaired in people with schizophrenia (PSZ), prior research has found no deficit in the ability to select one location and withdraw attention from another. PSZ and healthy control subjects (HCS) performed a stimulus detection task in which one, two, or all four peripheral target locations were cued. When one or two locations were cued, both PSZ and HCS responded faster when the target appeared at a cued than uncued location. However, increases in the number of validly cued locations had much more deleterious effects on performance for PSZ than HCS, especially for targets of low contrast whose detection was more dependent on attention. PSZ also responded more slowly in trials with four cued locations relative to trials with one or two invalidly cued locations. Thus, visuospatial attention deficits in schizophrenia arise when broad monitoring is required rather than when attention must be focused narrowly.

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.