Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia.

BACKGROUND: Abnormal smooth pursuit eye movement (SPEM) in schizophrenic patients is a well known phenomenon, but the neurophysiological mechanisms underlying the deficit are unknown. Nicotine temporarily improves SPEM and has been associated with reduced hippocampal hemodynamic activity in schizophrenics. Nicotine's effect on brain activity in control subjects performing SPEM has not been studied. The purpose of this work was to determine if nicotine differentially affects brain activity in schizophrenic and control subjects during pursuit eye tracking. METHODS: 16 subjects with schizophrenia and 16 control subjects underwent functional MR imaging during SPEM after receiving placebo or nicotine gum. Four brain regions were analyzed for main effects of group, drug, and interactions: hippocampus, cingulate gyrus, frontal eye fields, and area MT. RESULTS: Nicotine reduced hippocampal activity in both groups, but the effect was greater in control subjects. A group by drug interaction was observed in the anterior cingulate gyrus, where nicotine decreased activity in control subjects and increased activity in schizophrenic subjects. There were no significant effects of group, drug, or interactions in frontal eye fields or area MT. CONCLUSIONS: Nicotine may improve SPEM performance in people with schizophrenia through cholinergic stimulation of the hippocampus and cingulate gyrus. Potential mechanisms include improved inhibitory function and attention.     

Management of attentional resources in within-modal and cross-modal divided attention tasks: an fMRI study

In the present study, we were interested in distinguishing the cortical representations of within-modal and cross-modal divided attention tasks by using functional magnetic resonance imaging. Sixteen healthy male subjects aged between 21 and 30 years underwent two within-modal (auditory/auditory, visual/visual) and one cross-modal (auditory/visual) divided attention task, as well as related selective attention control conditions. After subtraction of the corresponding control task the three divided attention tasks, irrespective of sensory modality, revealed significant activation in a predominantly right hemisphere network involving the prefrontal cortex, the inferior parietal cortex, and the claustrum. Under the cross-modal condition, however, the frontal and parietal activation was more extended and more bilateral and there also was stronger right hemisphere activation of the anterior cingulate cortex and the thalamus. In comparison to the within-modal conditions additional bilateral frontal and left inferior parietal activation was found for the cross-modal condition. The supplementary fronto-parietal, anterior cingulate cortex, and thalamus activation in the auditory/visual condition could be argued to reflect an additional demand for coordination of two ongoing cross-modal cognitive processes.     

Attention profile in schizophrenia compared with depression: differential effects of processing speed,selective attention and vigilance

OBJECTIVE: The aim of the study is to investigate whether subjects with schizophrenia and major depression display attention deficits for different reasons. METHOD: Subjects with schizophrenia (n = 53), recurrent major depression (n = 50) and normal controls (n = 50) were administered with 11 measures of processing speed, selective attention and vigilance. Indices of basal speed, speeded attention, non-speeded attention and vigilance were computed. RESULTS: Both clinical groups were impaired on all chronometric tests. The schizophrenic subjects were also more impaired on speeded attention compared with basal processing speed. Only the schizophrenics were impaired on the non-speeded measures of selective attention. Compared with the schizophrenics, the depressives showed a decrement in vigilance. CONCLUSION: Reduced performance on attention tests in major depression is because of a non-specific speed reduction and loss of vigilance consistent with lack of effort. In addition to generally impaired processing speed, the schizophrenic subjects exposed a deficit in selective attention, indicating executive dysfunction.     

Human prefrontal and sensory cortical activity during divided attention tasks

In our natural environment, the ability to divide attention is essential since we attend simultaneously to a number of sensory modalities, e.g., to visual and auditory stimuli. In this study, functional magnetic resonance imaging (fMRI) was used to study brain activation while a divided attention task was performed. Brain activation was also assessed under selective attention. Fourteen healthy male subjects aged between 19 and 28 years underwent fMRI studies using gradient EPI sequences. Cingulate activation was evident in all attention tasks. Focusing attention on one modality (visual or auditory) increased the activity in the corresponding primary and secondary sensory area. When attention is divided between both modalities, the activation in the sensory areas is decreased, possibly due to a limited capacity of the system for controlled processing. Left prefrontal activation, however, was evident selectively during the divided attention task. The present results suggest that this area may be important in the execution of controlled processing when attention is divided between two sources of information. These results support the view that the prefrontal cortex is involved in the central executive system and controls attention and information flow.     

Modulation of auditory cortex activation by sound presentation rate and attention

We studied the effects of sound presentation rate and attention on auditory supratemporal cortex (STC) activation in 12 healthy adults using functional magnetic resonance imaging (fMRI) at 3 T. The sounds (200 ms in duration) were presented at steady rates of 0.5, 1, 1.5, 2.5, or 4 Hz while subjects either had to focus their attention to the sounds or ignore the sounds and attend to visual stimuli presented with a mean rate of 1 Hz. Consistent with previous observations, we found that both increase in stimulation rate and attention to sounds enhanced activity in STC bilaterally. Further, we observed larger attention effects with higher stimulation rates. This interaction of attention and presentation rate has not been reported previously. In conclusion, our results show both rate-dependent and attention-related modulations of STC indicating that both factors should be controlled, or at least addressed, in fMRI studies of auditory processing.     

The effects of nicotine on specific eye tracking measures in schizophrenia.

BACKGROUND: The role of neuronal nicotinic receptors in the etiology and pathophysiology of schizophrenia has been suggested by postmortem findings as well as by linkage analysis implicating chromosome 15q14, the region where the alpha-7 nicotinic receptor gene is located. In addition, drug probe studies show that acute nicotine administration reverses sensory gating and eye-tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention.METHODS: Twenty nine subjects with schizophrenia (15 smokers and 14 nonsmokers), and 26 healthy comparison subjects (15 smokers and 11 nonsmokers) completed testing. The effects of 1 mg of nicotine, administered by nasal spray, on smooth pursuit initiation, pursuit maintenance, and predictive pursuit were examined.RESULTS: Nicotine significantly improved eye acceleration during smooth pursuit initiation in both smoker and nonsmoker patients but had no effects in healthy subjects. The fact that patient initiation eye acceleration in response to nicotine was significantly higher than in healthy subjects suggests that the lack of effect in healthy subjects was not due to ceiling effects. Nicotine significantly improved pursuit gain during maintenance at a target velocity of 18.7 deg/sec. There were no effects of nicotine on visually guided and memory saccades, or visual attention (d' from a continuous performance task).CONCLUSIONS: Nicotine showed differential effects in schizophrenic patients compared to healthy subjects. These effects of nicotine were unlikely the result of differences in vigilance or sustained attention, because saccadic peak velocity, a sensitive measure of vigilance, and continuous performance task measures were not affected by nicotine. These findings are not thought to be an artifact of nicotine withdrawal effects at baseline, because the abstinence period was very short, and there were similar effects of nicotine on initiation in nonsmoker patients. These findings suggest an abnormality in neuronal nicotinic system functioning in schizophrenic patients.     

A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia

Working memory impairment is one of the cardinal cognitive disturbances in schizophrenia and considerable evidence suggests that it can be traced to functional alterations in the brain. The exact allocation of specific deficits to regional specific dysfunctions, however, remains elusive. The aim of this study was to examine the functional integrity of three distinguishable brain systems underlying maintenance-related subprocesses of working memory (articulatory rehearsal, non-articulatory maintenance of phonological information, maintenance of visuospatial information) in patients with schizophrenia. Using an experimental paradigm, which had been designed to selectively activate these different brain systems, we assessed the brain activation of patients and controls with functional magnetic resonance imaging. Compared with controls, patients showed reduced activation of the fronto-opercular, intraparietal and anterior cingulate cortex during the non-articulatory maintenance of phonological information, as well as attenuated deactivation of the hippocampus. Additionally, we found prefrontal activation to depend critically on the patients' current symptom status. During visuospatial maintenance, patients showed impaired activation of the superior parietal, temporal and occipital cortex, combined with enhanced activation of the frontal eye field and the inferior parietal cortex. No abnormal activations were observed during the articulatory rehearsal task. All activation differences were independent of group differences in task performance. Our fine-grained analysis of dysfunctions in particular aspects of working memory circuitry provides evidence for a differential impairment of the brain systems supporting working memory subcomponents in schizophrenia and extends knowledge of the relationship between cognitive deficits, brain activation abnormalities and symptoms in schizophrenia.     

Activation of brainstem and midbrain nuclei during cognitive control in medicated patients with schizophrenia

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event‐related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations.     

Nicotine effects on brain function and functional connectivity in schizophrenia.

BACKGROUND: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity. METHODS: Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning twice, once after placement of a placebo patch and once after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load. RESULTS: During the most difficult (dichotic 2-back) task condition, nicotine improved performance of schizophrenic subjects and worsened performance of control subjects. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance. CONCLUSIONS: In tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance.     

Neural effects of nicotine during auditory selective attention in smokers: an event-related potential study

Acute nicotine has been found to improve task performance in smokers after smoking abstinence, but the attentional processes mediating these improvements are unclear. Since scalp-recorded event-related potentials (ERPs) have been shown to be sensitive indicators of selective attention, the effects of acutely administered nicotine were examined on ERPs and concomitant behavioural performance measures in an auditory selective attention task. Ten (6 males) overnight smoking-abstinent cigarette smokers received nicotine gum (4 mg) in a randomized, double-blind, placebo-controlled, crossover design. In a dichotic listening task [which required participants to attend and detect (target) deviant stimuli in one ear and to ignore similar stimuli in the other ear] which included ERP recordings and assessment of response speed and accuracy measures, nicotine gum failed to alter behavioural performance or amplitudes of ERP components sensitive to selective attention [reflected in the N100 and negative difference (Nd) component] or to pre-attentive detection of acoustic change [reflected in the mismatch negativity (MMN) component]. However, nicotine did influence the speed of these voluntary selective processes, as reflected by shortened latencies of the early Nd component. The findings are discussed in relation to the stimulus filter theory of smoking, and with respect to nicotine's actions on involuntary and controlled aspects of selective attention processes.     

Refixation saccades and attention in schizophrenia

Saccadic refixation eye movements of 20 schizophrenic, 20 hospitalized nonpsychotic, and 20 normal subjects were compared in two repetitive fixation tasks with high and low target information. Although no differences emerged among groups in the overall frequency or size of saccades, the average and peak velocity of saccades was slower for schizophrenics than for normals. The velocity of saccades for the hospitalized nonpsychotic group was between that of schizophrenics and normals. To evaluate this finding further, saccades in the first two stimulus cycles were examined. The average and peak velocity of saccades was found to be significantly slower for schizophrenics than for normals. Again, the velocity of saccades for hospitalized nonpsychotic subjects was between that of schizophrenics and normals. Moreover, the size of saccades during the first two cycles was smaller for the schizophrenic than for other subject groups. Embedded alphanumeric information in the fixation target generally resulted in increased velocity of saccades for all subjects. The results were interpreted as evidence for an attentional deficit in schizophrenia. Specifically, schizophrenic subjects appeared to be less able to utilize peripheral visual information than hospitalized or normal subjects.     

Functional neuroanatomy of sustained attention in schizophrenia: contribution of parietal cortices

Deficits in sustained attention have been frequently described in schizophrenia. The neuroanatomical basis reported previously have included altered levels of activation in cingulate and prefrontal cortex, but the contribution of further regions remains unclear. We explored the full neuroanatomy underlying the sustained attentional deficits observed in naïve schizophrenics compared with controls. Participants included 10 controls and 11 patients. The experimental design included rest, auditory stimulation using clicks, and two counting tasks. Subjects were instructed to mentally count the clicks, and then to count forward at the same frequency they heard previously when listening to the clicks. Relative cerebral blood flow (relCBF) was measured by means of PET ¹⁵O‐water. Differences were observed between both groups at superior temporal cortex, superior parietal gyrus, and cerebellum during tasks requiring listening. During all counting conditions, additionally to supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPCF), precentral gyrus, cingulate, cerebellum, and inferior parietal (IP) gyrus, patients engaged other frontal structures including inferior, medial, and superior frontal areas. When counting with no auditory stimulation (C; requires components of working memory and time estimation), significant differences were observed in the level of activation of frontal and IP regions. Our naïve patients presented abnormal activation of auditory associative pathways. They failed to activate prefrontal and parietal regions at a similar level during tasks requiring increased cognitive effort, and they required a higher activation of inferior frontal regions to properly respond to cognitive demands. Hum. Brain Mapping 17:116–130, 2002. © 2002 Wiley‐Liss, Inc.     

Unseen fearful faces promote amygdala guidance of attention

Little is known about the network of brain regions activated prior to explicit awareness of emotionally salient social stimuli. We investigated this in a functional magnetic resonance imaging study using a technique that combined elements of binocular rivalry and motion flash suppression in order to prevent awareness of fearful faces and houses. We found increased left amygdala and fusiform gyrus activation for fearful faces compared to houses, despite suppression from awareness. Psychophysiological interaction analyses showed that amygdala activation was associated with task-specific (fearful faces greater than houses) modulation of an attention network, including bilateral pulvinar, bilateral insula, left frontal eye fields, left intraparietal sulcus and early visual cortex. Furthermore, we report an unexpected main effect of increased left parietal cortex activation associated with suppressed fearful faces compared to suppressed houses. This parietal finding is the first report of increased dorsal stream activation for a social object despite suppression, which suggests that information can reach parietal cortex for a class of emotionally salient social objects, even in the absence of awareness.     

Extended use of nicotine replacement therapy to maintain smoking cessation in persons with schizophrenia

This study was designed to determine the feasibility and efficacy of long-term nicotine replacement therapy (NRT) in helping persons with schizophrenia remain tobacco-free. Fifty smokers with a diagnosis of schizophrenia or schizo-affective disorder and whose symptoms had been stable for at least two months were enrolled in a program providing group support and NRT (patches) in individually adjusted doses set to maintain baseline nicotine intake. All participants attended weekly group support/motivation sessions. Smoking activity was determined by measuring carbon monoxide levels in expired air. Participants who quit tobacco use completely during the first three months were entered into a single-blind phase in which they received either placebo or active nicotine patches for up to six additional months, along with biweekly group sessions. Sixty days into the open-label phase, 66% of the subjects had reduced their use of tobacco by at least 75%. After 90 days of open-label treatment, 18 subjects (36%) were tobacco-free and qualified to enter the six-month, single-blind phase, eight on placebo and nine on active patches. A significantly greater proportion of those on placebo (8 of 8) compared with those on active patches (3 of 9) relapsed prior to completion of the 6-month period. This difference is statistically significant at the p = 0.009 level. The results of this study indicate that long-term use of NRT is feasible and effective for sustained tobacco-free success and may be an important strategy for reducing health risks due to tobacco use in this special population.     

Oddball and incongruity effects during Stroop task performance: a comparative fMRI study on selective attention

The aim of this fMRI study was to investigate and compare the neural mechanisms of selective attention during two different operationalizations of competition between task-relevant and task-irrelevant information: Stroop-incongruity and oddballs. For this purpose, we employed a Stroop-like oddball task in which subjects responded to the font size of presented word stimuli. Stroop-incongruity was created by (response-)incongruent word information while oddballs comprised low-frequency events in a task-irrelevant, unattended dimension. Thereby, in order to elucidate the influence of processing domain from which competition emanates, oddball conditions were created in two different attribute dimensions, color and word meaning. Either oddball condition was expected to evoke an orienting response, which participants would have to override in order to maintain adequate performance. Incongruent Stroop trials were expected to produce Stroop-interference so that subjects would have to override the predominant tendency to read and respond to word meaning. All competition conditions exhibited significantly prolonged reaction times compared to control trials, demonstrating that our experimental manipulation was indeed effective. fMRI data analyses delineated two discriminative components of competition: one component mainly related to motor preparation and another, primarily attentional component. Regarding the first, Stroop-interference increased activation mainly in regions implicated in motor control or response preparation. Regarding the second, Word-oddballs increased activation in a frontoparietal "attention network". Furthermore, Word-oddballs and Color-oddballs exhibited striking activation overlap mainly in prefrontal regions but also in posterior processing areas. Here, the data emphasized a prominent role of posterior lateral PFC in implementing top-down attentional control.     

Parietal cortex integrates contextual and saliency signals during the encoding of natural scenes in working memory

The Brief presentation of a complex scene entails that only a few objects can be selected, processed indepth, and stored in memory. Both low‐level sensory salience and high‐level context‐related factors (e.g., the conceptual match/mismatch between objects and scene context) contribute to this selection process, but how the interplay between these factors affects memory encoding is largely unexplored. Here, during fMRI we presented participants with pictures of everyday scenes. After a short retention interval, participants judged the position of a target object extracted from the initial scene. The target object could be either congruent or incongruent with the context of the scene, and could be located in a region of the image with maximal or minimal salience. Behaviourally, we found a reduced impact of saliency on visuospatial working memory performance when the target was out‐of‐context. Encoding‐related fMRI results showed that context–congruent targets activated dorsoparietal regions, while context–incongruent targets de‐activated the ventroparietal cortex. Saliency modulated activity both in dorsal and ventral regions, with larger context‐related effects for salient targets. These findings demonstrate the joint contribution of knowledge‐based and saliency‐driven attention for memory encoding, highlighting a dissociation between dorsal and ventral parietal regions. Hum Brain Mapp 36:5003–5017, 2015. © 2015 Wiley Periodicals, Inc .     

Neuronal modulation of auditory attention by informative and uninformative spatial cues

Sounds provide important information about the spatial environment, including the location of approaching objects. Attention to sounds can be directed through automatic or more controlled processes, which have been well studied in the visual modality. However, little is known about the neural underpinnings of attentional control mechanisms for auditory signals. We studied healthy adults who underwent event-related FMRI while performing a task that manipulated automatic and more controlled auditory orienting by varying the probability that cues correctly predicted target location. Specifically, we examined the effects of uninformative (50% validity ratio) and informative (75% validity ratio) auditory cues on reaction time (RT) and neuronal functioning. The stimulus-onset asynchrony (SOA) between the cue and the target was either 100 or 800 ms. At the 100 ms SOA, RT was faster for valid than invalid trials for both cue types, and frontoparietal activation was greater for invalid than valid trials. At the 800 ms SOA, RT and functional activation depended on whether cues were informative or uninformative, and whether cues correctly or incorrectly predicted the target location. Contrary to our prediction, activation in a frontoparietal network was greater for uninformative than informative cues across several different comparisons and at both SOAs. This finding contrasts with similar research of visual orienting, and suggests that the auditory modality may be more biased toward automatic shifts of attention following uninformative cues.     

Anatomical evidence of impaired feedforward auditory processing in schizophrenia.

BACKGROUND: Somal volumes of pyramidal cells are reduced within feedforward but not feedback circuits in areas 41 and 42 of the auditory cortex of subjects with schizophrenia. Because neuronal somal volume depends on both the number of axonal terminations onto and furnished by the neuron, we hypothesized that axon terminal densities are reduced in feedforward but not feedback auditory pathways in subjects with schizophrenia. METHODS: We used stereologic methods to quantify the density of a marker of axon terminals, synaptophysin-immunoreactive (SY-IR) puncta, in areas 41 and 42 of 15 subjects with schizophrenia and matched normal comparison subjects. The effect of long-term haloperidol exposure on density of SY-IR puncta was similarly evaluated in nonhuman primates. RESULTS: Synaptophysin-immunoreactive puncta density was 13.6% lower in deep layer 3 of area 41 in the schizophrenia subjects but was not changed in layer 1 of area 41 or in deep layer 3 of area 42. Density of SY-IR puncta did not differ between haloperidol-exposed and control monkeys. CONCLUSIONS: Reduction of SY-IR puncta density is selective for feedforward circuits within primary auditory cortex of subjects with schizophrenia. This deficit may contribute to impairments in auditory sensory processing in this disorder.