Sustained brain activation supporting stop-signal task performance.

Stop-signal paradigms operationalize a basic test of goal-directed behaviour whereby an overarching stop goal that is performed intermittently must be maintained throughout ongoing performance of a reaction time go task (go goal). Previous studies of sustained brain activation during stop-signal task performance in humans did not observe activation of the dorsolateral prefrontal cortex (DLPFC) that, in concert with the parietal cortex, is known to subserve goal maintenance. Here we explored the hypothesis that a DLPFC and parietal network has a key role in supporting ongoing stop-signal task performance. We used a blocked functional magnetic resonance imaging design that included blocks of trials containing typical stop-signal paradigm stimuli that were performed under three conditions: Stop condition, which required reaction time responding to go stimuli and inhibition of cued responses upon presentation of a stop signal; Go condition, identical except that the tone was ignored; and Passive condition, which required only quiescent attention to stimuli. We found that, whereas a distributed corticothalamic network was more active in Stop compared with Go, only the right DLPFC and bilateral parietal cortex survived after masking that contrast with Stop compared with Passive. These findings indicate that sustained activation of a right dominant frontoparietal network supports stop goal processes during ongoing performance of the stop-signal task.

The spatial and temporal dynamics of anticipatory preparation and response inhibition in task-switching.

We investigated ERP and fMRI correlates of anticipatory preparation and response inhibition in a cued task-switching paradigm with informatively cued, non-informatively cued and no-go trials. Cue-locked ERPs showed evidence for a multicomponent preparation process. An early cue-locked differential positivity was larger for informative vs. non-informative cues and its amplitude correlated with differential activity for informatively vs. non-informatively cued trials in the dorsolateral prefrontal cortex (DLPFC), consistent with a goal activation process. A later differential positivity was larger for informatively cued switch vs. repeat trials and its amplitude correlated with informatively cued switch vs. repeat activity in the posterior parietal cortex (PPC), compatible with a category-response (C-R) rule activation process. No-go trials elicited a frontal P3, whose amplitude was negatively correlated with activity in the ventrolateral prefrontal cortex (VLPFC) and basal ganglia motor network, suggesting that a network responsible for response execution was inhibited in the course of a no-go trial. These findings indicate that anticipatory preparation in task-switching is comprised of at least two processes: goal activation and C-R rule activation. They also support a functional dissociation between DLPFC and VLPFC, with the former involved in top-down biasing and the latter involved in response inhibition.

Reconsidering electrophysiological markers of response inhibition in light of trigger failures in the stop-signal task.

This study investigates the neural correlates underpinning response inhibition using a parametric ex-Gaussian model of stop-signal task performance, fit with hierarchical Bayesian methods, in a large healthy sample (N = 156). The parametric model accounted for both stop-signal reaction time (SSRT) and trigger failure (i.e., failures to initiate the inhibition process). The returned SSRT estimate (SSRTEXG3 ) was attenuated by ≈65 ms compared to traditional nonparametric SSRT estimates (SSRTint ). The amplitude and latency of the N1 and P3 event-related potential components were derived for both stop-success and stop-failure trials and compared to behavioral estimates derived from traditional (SSRTint ) and parametric (SSRTEXG3 , trigger failure) models. Both the fronto-central N1 and P3 peaked earlier and were larger for stop-success than stop-failure trials. For stop-failure trials only, N1 peak latency correlated with both SSRT estimates as well as trigger failure and temporally coincided with SSRTEXG3 , but not SSRTint . In contrast, P3 peak and onset latency were not associated with any behavioral estimates of inhibition for either trial type. While the N1 peaked earlier for stop-success than stop-failure trials, this effect was not found in poor task performers (i.e., high trigger failure/slow SSRT). These findings are consistent with attentional modulation of both the speed and reliability of the inhibition process, but not for poor performers. Together with the absence of any P3 onset latency effect, our findings suggest that attentional mechanisms are important in supporting speeded and reliable inhibition processes required in the stop-signal task.

Maternal immune activation in mid-late gestation alters amphetamine sensitivity and object recognition, but not other schizophrenia-related behaviours in adult rats.

Maternal immune activation induced by Poly(I:C) administration is one of the most commonly used animal models of schizophrenia at present. Previous work from our team has demonstrated that some, but not all of the features often reported for maternal immune activation exposure in rodents can be observed in rats exposed to maternal immune activation at mid or late gestation. To determine whether previous findings in our laboratory were due to these time points simply being less sensitive neurodevelopmental periods for rats with regard to maternal immune activation effects, we aimed to investigate whether maternal immune activation at an often-reported sensitive period (mid-late gestation, day 14) resulted in more behavioural features reflective of face validity for schizophrenia. We examined the behavioural outcomes of mid-late maternal immune activation on a battery of behavioural tests aimed at assessing validity for positive, negative and cognitive symptoms of schizophrenia. We found that rats exposed to maternal immune activation, compared to controls, exhibited enhanced sensitivity to the locomotor-stimulating effects of amphetamine and reduced exploration of novel objects. These findings present a unique profile of effects, different to what has already been established for the same time point in rats, and different to what we had found at earlier and later time points. This work, among others in the literature, highlights the varying nature of models of maternal immune activation and we submit that it is essential for laboratories to characterise their models of maternal immune activation on behaviour rather than assuming that the effects from one laboratory apply in their own.

Late deviance detection in rats is reduced, while early deviance detection is augmented by the NMDA receptor antagonist MK-801.

One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the amplitude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP amplitudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.

Auditory prediction errors as individual biomarkers of schizophrenia.

Schizophrenia is a complex psychiatric disorder, typically diagnosed through symptomatic evidence collected through patient interview. We aim to develop an objective biologically-based computational tool which aids diagnosis and relies on accessible imaging technologies such as electroencephalography (EEG). To achieve this, we used machine learning techniques and a combination of paradigms designed to elicit prediction errors or Mismatch Negativity (MMN) responses. MMN, an EEG component elicited by unpredictable changes in sequences of auditory stimuli, has previously been shown to be reduced in people with schizophrenia and this is arguably one of the most reproducible neurophysiological markers of schizophrenia. EEG data were acquired from 21 patients with schizophrenia and 22 healthy controls whilst they listened to three auditory oddball paradigms comprising sequences of tones which deviated in 10% of trials from regularly occurring standard tones. Deviant tones shared the same properties as standard tones, except for one physical aspect: 1) duration - the deviant stimulus was twice the duration of the standard; 2) monaural gap - deviants had a silent interval omitted from the standard, or 3) inter-aural timing difference, which caused the deviant location to be perceived as 90° away from the standards. We used multivariate pattern analysis, a machine learning technique implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) to classify images generated through statistical parametric mapping (SPM) of spatiotemporal EEG data, i.e. event-related potentials measured on the two-dimensional surface of the scalp over time. Using support vector machine (SVM) and Gaussian processes classifiers (GPC), we were able classify individual patients and controls with balanced accuracies of up to 80.48% (p-values = 0.0326, FDR corrected) and an ROC analysis yielding an AUC of 0.87. Crucially, a GP regression revealed that MMN predicted global assessment of functioning (GAF) scores (correlation = 0.73, R2 = 0.53, p = 0.0006).

Differential impairments of selective attention due to frequency and duration of cannabis use.

The evidence for long-term cognitive impairments associated with chronic use of cannabis has been inconclusive. We report the results of a brain event-related potential (ERP) study of selective attention in long-term cannabis users in the unintoxicated state. Two ERP measures known to reflect distinct components of attention were found to be affected differentially by duration and frequency of cannabis use. The ability to focus attention and filter out irrelevant information, measured by frontal processing negativity to irrelevant stimuli, was impaired progressively with the number of years of use but was unrelated to frequency of use. The speed of information processing, measured by the latency of parietal P300, was delayed significantly with increasing frequency of use but was unaffected by duration of use. The results suggest that a chronic buildup of cannabinoids produces both short- and long-term cognitive impairments.

Brain potential evidence for an auditory sensory memory deficit in schizophrenia.

OBJECTIVE: The multiple disorders of selective attention found in schizophrenia could be secondary to disturbances in sensory processing. The authors investigated this possibility by using an event-related potential index of auditory sensory memory, called "mismatch negativity." METHOD: Medicated (N = 11) and neuroleptic-free (N = 11) patients with schizophrenia and patients with bipolar affective disorder (N = 11) were compared with age- and sex-matched healthy comparison subjects. Auditory stimuli were presented while the subjects were distracted with an attention-demanding visual task. Event-related potentials were elicited by infrequently occurring auditory stimuli (deviants) and by regularly presented auditory stimuli (standards), which differed slightly in duration. The difference in amplitude between the event-related potentials elicited by the deviant and standard stimuli was the mismatch negativity. RESULTS: The amplitude of the mismatch negativity was significantly lower in both groups of schizophrenic patients than in the healthy comparison subjects. Mismatch negativity amplitude was significantly correlated with ratings of negative schizophrenic symptoms but not with positive symptoms. Compared with the matched comparison subjects, the bipolar affective disorder patients did not show lower amplitude of mismatch negativity. There was a significant negative correlation between age and mismatch negativity amplitude. CONCLUSIONS: The abnormal auditory sensory memory processing indicated by low mismatch negativity amplitude in the schizophrenic patients cannot be accounted for by neuroleptic medication status. Because this abnormality was significantly related to measures of negative symptoms only, it may be a chronicity marker or reflect a predisposition to the development to schizophrenia. These findings implicate the auditory cortex in the pathophysiology of schizophrenia.

Processing of tactile stimuli and implications for the reading disabled.

A finger localization task was used to investigate interhemispheric transfer of tactile information and the processing of sequential tactile information in 7- and 9-year-old "average" readers and 9-year-old reading disabled boys. The performance of the reading disabled group on interhemispheric transfer and sequential processing was comparable to or worse than the 7-year-old average readers. Significant correlations linked the reading disabled boys' performance on the finger localisation task with their reading skills, performance on perceptual/motor tasks and knowledge of order in the time domain. The results are interpreted in terms of delayed myelination of interhemispheric and intrahemispheric pathways in the reading disabled.

Human brain regions required for the dividing and switching of attention between two features of a single object.

This combined PET and ERP study was designed to identify the brain regions activated in switching and divided attention between different features of a single object using matched sensory stimuli and motor response. The ERP data have previously been reported in this journal [64]. We now present the corresponding PET data. We identified partially overlapping neural networks with paradigms requiring the switching or dividing of attention between the elements of complex visual stimuli. Regions of activation were found in the prefrontal and temporal cortices and cerebellum. Each task resulted in different prefrontal cortical regions of activation lending support to the functional subspecialisation of the prefrontal and temporal cortices being based on the cognitive operations required rather than the stimuli themselves.

An exploration of varieties of visual attention: ERP findings.

A set of five tasks was designed to examine dynamic aspects of visual attention: selective attention to color, selective attention to pattern, dividing and switching attention between color and pattern, and selective attention to pattern with changing target. These varieties of visual attention were examined using the same set of stimuli under different instruction sets; thus differences between tasks cannot be attributed to differences in the perceptual features of the stimuli. ERP data are presented for each of these tasks. A within-task analysis of different stimulus types varying in similarity to the attended target feature revealed that an early frontal selection positivity (FSP) was evident in selective attention tasks, regardless of whether color was the attended feature. The scalp distribution of a later posterior selection negativity (SN) was affected by whether the attended feature was color or pattern. The SN was largely unaffected by dividing attention across color and pattern. A large widespread positivity was evident in most conditions, consisting of at least three subcomponents which were differentially affected by the attention conditions. These findings are discussed in relation to prior research and the time course of visual attention processes in the brain.

Do perceived loudness cues contribute to duration mismatch negativity (MMN)?

This study explored the contribution of perceived loudness cues to mismatch negativity produced in response to a 125 ms duration deviant tone among a regular sequence of 50 ms standard tones. Each individual was required to adjust the intensity of a 125 ms tone until it matched the perceived loudness of a 50 ms tone. The mismatch negativity produced to the duration deviant presented at the same intensity as the standard was contrasted with that produced to the same deviant at each individual's perceived loudness equivalence. Despite detectable difference perceived loudness (approximately 1.3 dB), adjusting the intensity of the deviant tone did not significantly reduce mismatch negativity amplitude to the duration deviant. Results are discussed with reference to temporal window of integration.

Facilitation of the N1 peak of the auditory ERP at short stimulus intervals.

Event-related potentials (ERP) were recorded to 1 kHz tones presented at random stimulus onset asynchronies (SOA) between 100 and 1000 ms. The Adjar correction procedure was employed to overcome waveform distortion resulting from previous response overlap. The results showed dramatic enhancements of the N1 peak when SOA was reduced to 100-300 ms, showing a reversal of the traditional amplitude by SOA function obtained by previous ERP research employing SOAs > 500 ms, and replicating similar enhancements of the magnetic counterpart of the N1 (N100m). The results are discussed in terms of the utility of the traditional 'refractoriness' account of the sensitivity of the N1 to SOA.

Do loudness cues contribute to duration mismatch negativity reduction in schizophrenia?

The present study explored duration mismatch negativity (MMN) reduction in schizophrenia. Duration MMN studies usually employ tones of very short duration (< 200 ms). For stimuli < 200 ms in duration, an increment in duration is accompanied by an increase in perceived loudness. It was previously proposed that the effectiveness of duration MMN in revealing MMN reduction in schizophrenia might be explained by patients being insensitive to loudness cues and duration increments. In this study we equated loudness cues in a typical duration MMN paradigm and explored the effect of this manipulation on MMN amplitude reduction in schizophrenia. The manipulation had little effect on a healthy comparison group but had a marked effect on the MMN generated in the patient group who produced a significantly smaller MMN response to the regular duration deviant than to that in the equated loudness condition. This result was interpreted as demonstrating that patients exhibit a very marked insensitivity to duration increments.

Association between reduced duration mismatch negativity (MMN) and raised temporal discrimination thresholds in schizophrenia.

OBJECTIVE: The event-related potential known as mismatch negativity (MMN) is elicited whenever the auditory system detects a change against an invariant background of stimulation. A reduction in mismatch negativity is well established in schizophrenia. The present study explored the association between reduced duration mismatch negativity in schizophrenia and behavioural measures of temporal discrimination. METHOD: Mismatch negativity amplitude to duration increments (125 vs. 50 ms) was compared between individuals with schizophrenia and healthy controls. Mismatch negativity amplitude was also related to two behavioural measures of temporal discrimination (silent and filled intervals) for detecting changes in stimuli of similar duration. RESULTS: Patients produced higher discrimination threshold estimates and smaller amplitude mismatch negativity responses to temporally deviant stimuli. Temporal discrimination thresholds correlated with the amplitude of the phase reversal in mismatch negativity at the left mastoid such that patients who produced the highest thresholds produced the smallest mismatch response. CONCLUSIONS: Imprecise representations of the temporal properties of auditory stimuli can account for some of the reduction in mismatch negativity amplitude in some patients but additional factors clearly contribute. The results suggest that patients who do and do not exhibit temporal processing deficits on behavioural tasks produce different patterns of reduction in duration mismatch negativity.

ERP correlates of response inhibition to elemental and configural stimuli in a negative patterning task.

OBJECTIVE: The present experiment examined the ERP correlates of response inhibition to elemental and configural Nogo stimuli in a Go/Nogo task. DESIGN AND METHODS: Event-related potentials (ERPs) were recorded while 8 subjects completed a visual Go/Nogo task. Nogo stimuli required the inhibition of a response to stimuli that differed from Go stimuli (A+, B+) either on the basis of each of two physical features (elemental Nogo stimuli; CD-) or on the basis of the conjunction of features represented in the Go stimuli (configural Nogo stimuli; AB-). Behavioural data and ERP component measures (amplitude and latency) were analysed using analysis of variance. RESULTS: An enhanced N2 component and an enhanced fronto-centrally distributed P3 component were elicited following elemental Nogo stimuli relative to Go stimuli, consistent with a number of studies examining ERPs during Go/Nogo tasks. In contrast, an enhanced late frontal negative/parietal positive slow wave was elicited following configural Nogo stimuli relative to Go stimuli. CONCLUSIONS: These results cast doubt on the interpretation of the N2 enhancement as reflecting response inhibition processes per se. The pattern of results was interpreted as providing support for the unique cue model of learning rather than the configural model of learning and was discussed in the context of a recent model of executive functioning.

Duration and frequency mismatch negativity in schizophrenia.

OBJECTIVES: The aim of the present study was to elucidate the reasons for apparent inconsistencies in the schizophrenia literature with respect to the mismatch negativity (MMN) waveform of the event-related potential (ERP). While most previous research has shown that MMN is reduced in schizophrenia, there are a small number of studies reporting that frequency MMN is not reduced. METHODS: We recorded ERPs to auditory stimuli with different frequencies and durations from patients with schizophrenia (N = 14) and control subjects (N = 17) of similar age and sex. MMNs to small but discriminable frequency deviants were contrasted with large frequency deviants and duration deviants. RESULTS: Only the MMN to duration deviants was significantly reduced in patients, although there was evidence of a similar trend for large frequency deviants. CONCLUSIONS: The results together with a review of the frequency MMN literature suggest that there are 3 variables which are important in determining whether patients exhibit a reduced MMN to frequency deviants: deviant probability, degree of deviance and interstimulus interval. The results also indicated that patients with schizophrenia may have particular deficits in processing the temporal properties of auditory stimuli. This finding has implications for the pathophysiology of the disorder as time-dependent processing is reliant on the integrity of an extensive network of brain areas consisting of auditory cortex, areas of pre-frontal cortex, the basal ganglia and cerebellum.

The effects of cigarette consumption on the Sternberg visual memory search paradigm.

AIM: To examine the performance of non-smokers (n = 24), light smokers (n = 22, mean 6.5 cigarettes per day) and heavy smokers (n = 19, mean 23 cigarettes per day) on the Sternberg memory search task. DESIGN: A repeated-measures, counterbalanced design was used with one between-subject factor, status (heavy, light or non-smoker) and two within-subject factors, condition (12 hours abstinence or ad libitum smoking) x time (pre- or post-cigarette). FINDINGS: Heavy smokers in the pre-cigarette abstinent session had significantly slower reaction times, movement times and higher intercepts (a measure of factors contributing to performance other than rate of memory scan) than non-smokers. After smoking these differences were removed. CONCLUSIONS: This suggests that rather than improving performance smoking ameliorates a deficit in certain measures of the Sternberg task produced by abstinence. Under ad libitum conditions improvements in performance were attributed to practice. Across all within-subject conditions, there were no significant main effects of smoking status, and this result was consistent with the lack of relationship between measures of saliva continine and expired air carbon monoxide and performance. These data do not support the view that non-abstinent smokers differ from non-smokers in the performance of the Sternberg memory search procedure.

Further evidence for a deficit in switching attention in schizophrenia.

In this study, sustained, selective, divided, and switching attention, and reloading of working memory were investigated in schizophrenia by using a newly developed Visual Attention Battery (VAB). Twenty-four outpatients with schizophrenia and 24 control participants were studied using the VAB. Performance on VAB components was correlated with performance of standard tests. Patients with schizophrenia were significantly impaired on VAB tasks that required switching of attention and reloading of working memory but had normal performance on tasks involving sustained attention or attention to multiple stimulus features. Switching attention and reloading of working memory were highly correlated with Trails (B-A) score for patients. The decline in performance on the switching-attention task in patients with schizophrenia met criteria for a differential deficit in switching attention. Future research should examine the neurophysiological basis of the switching deficit and its sensitivity and specificity to schizophrenia.

Early selective-attention effects on the evoked potential: a critical review and reinterpretation.

Recent research on the effect of selective attention on the N1, component of the evoked potential is reviewed. These studies are based on the finding of Hillyard Hink, Schwent and Picton (1973) that this component is selectively enhanced in response to attended stimuli when a very rapid rate of stimulus delivery is used. On the basis of the subsequent set of experiments, the conditions and limits of the existence of the auditory 'N1 effect' are now quite clear. Moreover, this finding has been extended to somatosensory and visual modalities. In the present review a detailed examination of these studies has suggested a re-interpretation of the N1 effect. According to this reinterpretation, it is not a 'true' N1 component which is enhanced but the effect is produced by a summation of a negative shift with the evoked-potential wave form. Under some conditions such as those involving a very fast rate of stimulus delivery, this effect commences very early, making the N1 component appear larger. It is suggested that this shift reflects orienting to, and further processing of, an input found relevant in a preliminary sensory analysis. Topographical evidence for this kind of interpretation is provided by several studies. This negative shift is, hence, associated with voluntary attention. Some of the reviewed studies have described a rather similar negative shift as a correlate of involuntary attention to rare stimuli among the much more frequent, 'standard', stimuli.