Relationship between carbohydrate-deficient transferrin, gamma-glutamyl transferase, and mean corpuscular volume levels and alcohol-related brain volume decreases in male drinkers.

OBJECTIVE: We investigated the association between mean corpuscular volume (MCV), carbohydrate-deficient transferrin (CDT), and gamma-glutamyl transferase (GGT) levels and gray and white brain matter in male drinkers to find out which if any of these biomarkers of alcohol consumption is indicative for alcohol-related differences in brain volume. METHOD: Plasma levels of CDT, GGT, and MCV and magnetic resonance imaging-determined brain gray and white matter volumes were assessed in 55 male drinkers. Current alcohol intake and lifetime alcohol intake were determined by self-report measures. The relationship between MCV, CDT, and GGT and brain volumes was explored using multiple linear regression analyses. RESULTS: There was a significant negative relationship between plasma GGT and MCV levels and gray matter volumes. Middle-aged male drinkers with highly elevated GGT and MCV levels (twice the standard deviation above the mean) have 4-12% less parietal and occipital gray matter than males with average GGT and MCV levels. There was no association between CDT levels and brain gray or white matter. CONCLUSIONS: Elevated GGT and MCV levels may be indicative of alcohol-related gray-matter decline in male drinkers. The link with GGT may reflect that elevated GGT levels are a sign of increased oxidative stress. The link with MCV levels may reflect a decreased oxygen transport to the brain.

Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude.

Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought. Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. Can haloperidol (D2 antagonist) counteract the disruptive effects of ketamine on psychophysiological parameters of human attention? In a randomized, double-blind, placebo-controlled experiment 18 healthy male volunteers received placebo/placebo, placebo/ketamine (0.3 mg/kg i.v.) and haloperidol (2 mg)/ketamine (0.3 mg/kg i.v.) on three separate test days, after which they were tested in an auditory selective-attention paradigm. Haloperidol/ketamine reduced task performance compared to placebo/placebo, while the task performance in these two treatments did not differ from placebo/ketamine. Furthermore, placebo/ketamine reduced processing negativity compared to both placebo/placebo and haloperidol/ketamine, while processing negativity did not differ between placebo/placebo and haloperidol/ketamine treatments. However, both placebo/ketamine and haloperidol/ketamine reduced P300 amplitude compared to placebo/placebo, while P300 amplitude did not differ between placebo/ketamine and haloperidol/ketamine treatments. The combined effects of haloperidol and ketamine reduced task performance, suggesting that this is dependent on dopaminergic D2 activity, probably in the prefrontal cortex. In addition, ketamine reduced both P300 amplitude and processing negativity. In contrast to the P300 amplitude, the disruptive effects of ketamine on processing negativity could be prevented by pretreatment with haloperidol. The current results suggest that ketamine reduced P300 amplitude by its antagonistic effect on glutamatergic activity, while it reduced processing negativity by its agonistic effect on dopaminergic D2 activity.

Chronic effects of low to moderate alcohol consumption on structural and functional properties of the brain: beneficial or not?

OBJECTIVE: Some studies suggest that the effects of low to moderate drinking (about 1-3 standard glasses of alcohol per day) on the brain and cognitive performance are positive. In the present study this hypothesis is investigated. METHODS: For this purpose studies on the effects of low to moderate drinking on brain structure (Magnetic Resonance Induction (MRI) studies) and on cognitive performance were analysed and discussed RESULTS: In MRI studies, a linear negative effect of alcohol consumption on brain volume was found. Furthermore, a linear decrease in grey matter concurring with a linear increase in white matter volumes as a function of number of drinks was reported in males, but not in females. Only in elderly low to moderate drinkers (aged > 65 years) there appeared to be an U-shaped relationship between alcohol consumption and white matter integrity (grade) on the one hand and cognition on the other hand. CONCLUSIONS: The changes reported in brain shrinkage, grey matter and white matter volume, as a result of low to moderate alcohol consumption sooner offer support for the contention that such drinking decreases brain health than for its beneficial effect. An exception might hold for elderly light and moderate drinkers where less white matter damage was found than in abstainers concurring with better cognitive performance. However, methodological problems impose limits on this conclusion.

Methylphenidate significantly improves driving performance of adults with attention-deficit hyperactivity disorder: a randomized crossover trial.

Although patients with attention-deficit hyperactivity disorder (ADHD) have reported improved driving performance on methylphenidate, limited evidence exists to support an effect of treatment on driving performance and some regions prohibit driving on methylphenidate. A randomized, crossover trial examining the effects of methylphenidate versus placebo on highway driving in 18 adults with ADHD was carried out. After three days of no treatment, patients received either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo and then the opposite treatment after a six to seven days washout period. Patients performed a 100 km driving test during normal traffic, 1.5 h after treatment administration. Standard deviation of lateral position (SDLP), the weaving of the car, was the primary outcome measure. Secondary outcome measurements included the standard deviation of speed and patient reports of driving performance. Driving performance was significantly better in the methylphenidate than in the placebo condition, as reflected by the SDLP difference (2.3 cm, 95% CI = 0.8-3.8, P = 0.004). Variation in speed was similar on treatment and on placebo (-0.05 km/h, 95% CI = -0.4 to 0.2, P = 0.70). Among adults with ADHD, with a history of a positive clinical response to methylphenidate, methylphenidate significantly improves driving performance.

Disentangling deficits in adults with attention-deficit/hyperactivity disorder.

CONTEXT: A lack of inhibitory control has been suggested to be the core deficit in attention-deficit/hyperactivity disorder (ADHD), especially in adults. This means that a primary deficit in inhibition mediates a cascade of secondary deficits in other executive functions, such as attention. Impaired stopping has been claimed to support the inhibition hypothesis. However, executive functions such as inhibition and attention are hard to disentangle. OBJECTIVE: To use event-related potentials in adult patients with ADHD to show that impaired stopping is associated with abnormalities of attention. DESIGN: The stop signal task was presented to 24 adults with ADHD combined subtype and 24 controls. Stop event-related potentials are distorted by overlap from event-related potentials to other stimuli in close temporal proximity, but we applied a method (Adjar level 2) to effectively remove this overlap. RESULTS: In line with an inhibitory control deficit, the stop signal reaction time was longer in adults with ADHD (F(1,46) = 7.12, P<.01) whereas there was no significant difference for go stimulus reaction time. Overlap-free stop event-related potentials revealed smaller stop P3s in adults with ADHD (F(1,44) = 4.20, P<.05). In children with ADHD, this has been interpreted to reflect deficient inhibitory control. However, controls were also found to have larger early responses in the auditory cortex (N1) when stop signals resulted in successful stops, relative to failed stops, signifying increased attention (F(1,23) = 11.88, P<.01). This difference was completely absent in adults with ADHD. CONCLUSIONS: Disturbed attentional processing of the stop signal contributed to impaired stopping in adults with ADHD. This finding may have implications for treatment.

Prepulse inhibition and P50 suppression: commonalities and dissociations.

Patients with schizophrenia exhibit reduced levels of both prepulse inhibition of the startle reflex (PPI) and condition-test suppression of the P50 event-related potential. This study investigated the extent to which PPI and P50 suppression, which exhibit similar parametric sensitivities, are intrinsically auditory phenomena or can be induced cross-modally, and reflect common or distinct neural mechanisms of inhibition. PPI, N100, and P50 were assessed in 20 healthy male volunteers, using auditory test probes and both visual and auditory lead stimuli, separated by 100- or 500-ms interstimulus intervals (ISIs). PPI was found in the auditory-lead condition across the complete group, and with visual-lead stimuli in approximately half of the subjects. Intra-modal auditory PPI was significantly higher with the 100-ms ISI than with the 500-ms ISI. P50 suppression was found only with the 500-ms ISI, with no difference between the auditory and visual conditions. Source analyses revealed that suppression was associated with frontal cortical activity. N100 suppression was found only in the auditory condition, with no difference between 100- and 500-ms ISIs. Although both phenomena are considered to provide operational measures of gating, PPI and P50 suppression are differentially sensitive to ISI and therefore reflect partly different neural mechanisms. They are not intrinsically auditory phenomena, and both appear to involve frontal cortical activity. In contrast, N100 suppression is most likely based on refractory mechanisms intrinsic to the auditory system.

Moderate-to-heavy alcohol intake is associated with differences in synchronization of brain activity during rest and mental rehearsal.

In alcohol-dependent individuals, synchronization of brain activity is different from that in non-alcohol-dependent individuals as reflected by EEG differences at alpha and beta frequencies (8-30 Hz). These EEG differences may not only be related to long-term alcohol intake but also to genetic factors that are associated with alcohol dependence. Thus, it is not known what the pure effect of long-term alcohol intake on synchronization of brain activity is. Therefore, we investigated whether EEG synchronization differs between light (0.5-6 drinks per week), moderate (7-20 drinks per week), and heavy (21-53 drinks per week) drinkers. All participants (49 males and 47 females) were free of a personal and family history of alcohol dependence. Eyes-closed EEG was recorded at rest and during mental rehearsal of pictures. EEG synchronization was determined by computing Synchronization Likelihood for six frequency bands (0.5-4 Hz, 4-8 Hz, 8-12 Hz, 12-20 Hz, 20-30 Hz, 30-45 Hz). Both male and female heavy drinkers displayed a loss of lateralization in alpha (8-12 Hz) and slow-beta (12-20 Hz) synchronization. In addition, moderately and heavily drinking males had lower fast-beta (20-30 Hz) synchronization than lightly drinking males. It is concluded that both male and female drinkers who drink 21 alcoholic drinks per week or more have impaired synchronization of brain activity during rest and mental rehearsal at alpha and beta frequencies as compared to individuals who drink less. As individuals with a personal or family history of alcohol dependence were excluded, the confounding effects of genetic factors related to alcohol dependence on synchronization of brain activity were minimized.

Dose-related effect of methylphenidate on stopping and changing in children with attention-deficit/hyperactivity disorder.

PURPOSE: The effect of methylphenidate (MPH) on inhibitory control as assessed by the stop task in children with attention-deficit/hyperactivity disorder (ADHD) could be influenced by task difficulty and may be mediated by attention. SUBJECTS AND METHODS: Fifteen children with ADHD performed the stop and the change task after placebo, 0.5 and 1.0 mg/kg MPH in a within-subject design. RESULTS: Linear-trend analysis showed a similar effect of MPH in both tasks and a stronger effect for inhibitory control than for attention. Furthermore, a correlation was found between blood serum metabolites of norepinephrine and dopamine for attentional measures and inhibitory control measures, respectively. DISCUSSION AND CONCLUSION: In children with ADHD MPH could act primarily on inhibitory control, and is not influenced by task difficulty. Also, attention and inhibitory control could have differential pharmacological profiles.

Source analysis of the N2 in a cued Go/NoGo task.

Previous source analyses of event-related potential (ERP) data elicited in Go/NoGo tasks have suggested that the anterior cingulate cortex (ACC) plays an important role in response inhibition. So far, however, source models were derived for the difference wave Go stimulus minus NoGo stimulus. This difference wave is confounded with motor- and attention-related activity. To avoid these confounds, we alternatively derived source models for NoGo stimuli only. The problem of the NoGo-N2 being superimposed on a positive deflection was addressed in two ways. First, a baseline correction was applied using the time points just preceding and succeeding the NoGo-N2. Second, a separate source model was derived at the maximum amplitude of this positive deflection. Subjects were presented with a cued version of the continuous performance task (CPT; ABX). In a second study, the probability of the Go stimulus was gradually increased to heighten subjects' tendency to respond and, as a consequence, to enhance the amplitude of the NoGo-N2. The source models of the NoGo-N2 consistently indicated bilateral dipole pairs in medial frontal regions. This is in accordance with a generator in the anterior cingulate cortex.

Chronic effects of social drinking in a card-sorting task: an event related potential study.

OBJECTIVE: The Wisconsin Card Sorting Task (WCST) is one of the most widely used neuropsychological tests of frontal lobe function, which is thought to be affected by regular alcohol use. The present study used a computer-adapted version of the WCST to assess the effects of chronic alcohol consumption on the brain. METHODS: Participants (N=59) sorted cards according to an initially unknown sorting rule, which referred to shape, number, or color. The correctness of the chosen sorting rule was indicated by a feedback stimulus. This correct sorting rule had to be followed for a number of stimuli, and when it changed participants had to find out which rule had to be followed next. A distinction was made between early (correct sorting rule is unknown) and late trials (correct sorting rule is known and applied). To measure brain activity related during the task event related potentials (ERPs) were recorded to the target and feedback stimulus in light (N=14), moderate (N=16) and heavy (N=19) social drinkers and excessive alcohol users (N=10). RESULTS: No differences in number of series completed or the reaction time in each trial, were found between the four groups. In contrast, a mid-frontal N1 component in reaction to the feedback stimuli did reveal differences between the four groups. In the light and moderate drinkers, on early feedback trials the N1 was larger relative to late feedback trials, but this effect was absent in the heavy social drinkers and excessive drinkers. CONCLUSIONS: The reduced N1 effect with increasing alcohol intake could reflect abnormal allocation of attention or impaired conflict monitoring, possibly based on activity in the anterior cingulate cortex. SIGNIFICANCE: Heavy social drinking and excessive drinking leads to changes in the mid-frontal N1 during feedback trials of the WCST.

A meta-analytic review of stopping performance in attention-deficit/hyperactivity disorder: deficient inhibitory motor control?

This review discusses whether deficient inhibitory motor control is the core deficit of attention-deficit/hyperactivity disorder (ADHD). Inhibitory motor control is commonly assessed using the stop-signal paradigm. Since the last meta-analysis that was performed, 33 new studies have appeared. The current meta-analysis revealed a significant difference between ADHD patients and matched controls in stop latency (stop-signal reaction time) in both children and adults. Basic reaction time was significantly longer in children with ADHD, but not in adults, and there was a significant interaction between the elongation of the latency to stop and to respond in adults, but not in children. Deficient inhibitory motor control may be less crucial in children than in adults with ADHD.

The pure electrophysiology of stopping.

In the stop-signal task, subjects should withhold their response in a choice reaction time task when a stop-signal, usually a tone, is presented. Successful stops have been associated with event-related potentials (ERPs) featuring a larger frontocentral positivity relative to failed stops. The functional interpretation of this stop-P3 has been disputed, because stop-ERPs are distorted by overlap from ERPs elicited by preceding go-stimuli. We effectively removed confounding potentials with the 'adjacent response filter method (ADJAR)'. Confirming an interpretation in terms of response inhibition, the stop-P3 remained and overlap removal resulted in a more anterior distribution. As a new finding, the N1 was larger on trials with successful stops, which suggests that inhibitory performance at least partly depended on the ability to switch attention to the stop-signal. Finally, the parietal P3 tended to peak earlier for successful than for failed stops. This is in line with the Horse Race Model, which states that faster stop-processes have a higher chance of winning the race against the go-process.

Sources of auditory selective attention and the effects of methylphenidate in children with attention-deficit/hyperactivity disorder.

BACKGROUND: The aim of this study was to determine 1) whether abnormal auditory selective attention in children with attention-deficit/hyperactivity disorder (ADHD), as reflected in the processing negativity (PN) of the event-related potential, is related to impaired frontal functioning; and 2) how methylphenidate (MPh) affects attentional functioning in ADHD. METHODS: Sources of electrical brain activity were estimated in healthy control children, in ADHD children without medication, and in children with ADHD during a placebo-controlled medication trial involving MPh. RESULTS: The source models showed that the PN is generated in the auditory cortex. Children with ADHD showed less activity related to selective attention in this brain region. Administration of MPh resulted in more frontally located sources. CONCLUSIONS: The results showed no evidence for an important role of the frontal cortex in abnormalities in selective attention in children with ADHD. Also, the data did not indicate that MPh normalizes brain activity in these children.

Inhibition in children with attention-deficit/hyperactivity disorder: a psychophysiological study of the stop task.

BACKGROUND: The purpose of the study was to investigate and identify abnormal brain activity, as revealed by event-related potentials (ERPs) concurring with deficient inhibitory control in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Performance and ERPs from 16 children with ADHD and 16 control subjects were compared in the stop-signal paradigm. RESULTS: The ADHD children showed a lower inhibition percentage and their (estimated) response time to the stop signal was disproportionally longer compared to the slowing of reaction times to primary-task stimuli. In normal control subjects, fronto-central positivity (100-400 msec) after the onset of the stop-signal was larger in case of successful inhibition, relative to failed inhibition; this was less so in ADHD children. A late positive wave (500-700 msec), maximal at Oz on failed inhibition trials, and possibly related to error-detection, was smaller in ADHD children. CONCLUSIONS: These results point to abnormalities in brain processes involved in motor inhibition and error-detection in ADHD children.

Effects of alprazolam on driving ability, memory functioning and psychomotor performance: a randomized, placebo-controlled study.

Alprazolam is prescribed for the treatment of anxiety and panic disorder. Most users are presumably involved in daily activities such as driving. However, the effects of alprazolam on driving ability have never been investigated. This study was conducted to determine the effects of alprazolam (1 mg) on driving ability, memory and psychomotor performance. Twenty healthy volunteers participated in a randomized, double-blind, placebo-controlled crossover study. One hour after oral administration, subjects performed a standardized driving test on a primary highway during normal traffic. They were instructed to drive with a constant speed (90 km/h) while maintaining a steady lateral position within the right traffic lane. Primary performance measures were the Standard Deviation of Lateral Position (SDLP) and the Standard Deviation of Speed (SDS). After the driving test, subjective driving quality, mental effort, and mental activation during driving were assessed. A laboratory test battery was performed 2.5 h after treatment administration, comprising the Sternberg Memory Scanning Test, a Continuous Tracking Test, and a Divided Attention Test. Relative to placebo, alprazolam caused serious driving impairment, as expressed by a significantly increased SDLP (F(1,19) = 97.3, p <.0001) and SDS (F(1,19) = 30.4, p <.0001). This was confirmed by subjective assessments showing significantly impaired driving quality (F(1,19) = 16.4, p <.001), decreased alertness (F(1,19) = 43.4, p <.0001), decreased mental activation (F(1,19) = 5.7, p <.03) and increased mental effort during driving (F(1,19) = 26.4, p <.0001). Furthermore, alprazolam significantly impaired performance on the laboratory tests. In conclusion, alprazolam users must be warned not to drive an automobile or operate potentially dangerous machinery.

Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking.

The impairing effects on memory functioning after acute alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. A total of 48 healthy volunteers participated in a single-blind study comprising an evening (baseline) session, followed by a treatment administration (ethanol 1.4 g/kg or placebo), and a morning session. Memory was tested with a word-learning test (including immediate and delayed recall, and recognition). Further, a 45-min Mackworth clock test for measuring vigilance was included (parameters: number of hits and false alarms) and subjective alertness was assessed, to infer whether word-learning test findings reflect sedation or specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol group when compared to the placebo group (F(1,42)=6.0, p<0.02). In contrast, immediate recall and recognition were unimpaired in the alcohol group. In the morning session, relative to the placebo group, subjective alertness was significantly reduced in the alcohol group before and after the tests (F(1,44)=8.7, p<0.005; F(1,44)=13.3, p&<0.001, respectively). However, in the Mackworth clock test, the alcohol group and placebo group did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. Vigilance performance was not significantly affected, indicating that this memory impairment does not reflect sedation.

Normal P50 gating in children with autism.

BACKGROUND: An important characteristic of children with autism is their unusual reaction to stimuli, which may be related to problems in the filtering of sensory input. For this reason, sensory filtering was measured in children with autism using the P50 gating paradigm. METHOD: Twelve non-mentally retarded children with autism (i.e., having a DSM-IV diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified) and 11 healthy control children were tested for their ability to suppress P50, measured at the Cz electrode. RESULTS: No differences were found between the children with autism and the control children with regard to absolute P50 amplitudes and P50 suppression. CONCLUSION: The excitability of the neuronal substrate that causes P50 is normal in children with autism, as are the early, inhibitory processes related to P50 gating. These results distinguish between subjects with autism and subjects with schizophrenia, in whom sensory gating is abnormal.

Benzodiazepines have no effect on fear-potentiated startle in humans.

RATIONALE: Pre-clinical and clinical investigations have provided a great deal of evidence that the fear-potentiated startle paradigm represents a valid model for the objective assessment of emotional states of anxiety and fear. OBJECTIVE: The four studies presented in this report sought to further validate the "threat of shock" paradigm as a human analogue to fear-potentiated startle in rats, by examining the effect of benzodiazepine administration on both baseline and fear-potentiated startle. METHODS: Three studies, conducted at Utrecht University, evaluated the effects of oxazepam and of diazepam on baseline and fear-potentiated startle, whereas a fourth study, conducted at Yale University, evaluated the effect of diazepam on baseline, contextual and cue-specific fear-potentiated startle. The threat of shock paradigm consisted of verbal instruction about two visual cues (the threat cue predicted the possible administration of electric shock, the other predicted a safe period), followed by a series of presentations of these cues. During these conditions, acoustic startle stimuli were presented in order to elicit startle responses. The magnitude of the startle response was used to index the degree of fear or alarm experienced during the periods of threat and safety. The fourth study examined the effect of IV administration of diazepam in a similar threat of shock paradigm except that there were two additional context manipulations: electrode placement and darkness. RESULTS: None of the drug manipulations affected specific threat-cue potentiation of startle. However, reductions in baseline startle were observed. Further, startle potentiation by darkness was inhibited by diazepam. CONCLUSIONS: At least one type of fear-potentiated startle, i.e. potentiation by a cue-specific fear manipulation, is not susceptible to benzodiazepine treatment. In contrast, effects of manipulations more akin to anxiety (darkness, context) appear sensitive to benzodiazepines. Human experimental models differentiating between these cue specific and contextual responses are needed to shed more light on differences in the anatomy and pharmacology of anxiety disorders.

Driving ability after acute and sub-chronic administration of levocetirizine and diphenhydramine: a randomized, double-blind, placebo-controlled trial.

RATIONALE: Sedation following antihistamine use poses a danger to ambulant patients involved in daily activities such as driving. OBJECTIVE: To investigate effects of levocetirizine (5 mg), diphenhydramine (50 mg), and placebo on driving ability during normal traffic. METHODS: Forty-eight healthy volunteers participated in a double-blind, placebo-controlled, randomized clinical trial. Treatments were administrated on days 1, 2, 3 and 4, exactly 1.5 h before the start of the standardized driving test (performed on day 1 and day 4). In the standardized driving test, subjects were instructed to drive with a steady lateral position, while maintaining a constant speed (95 km/h). Primary parameter was the standard deviation of lateral position (SDLP; cm). Statistical analyses were performed separately for day 1 and day 4, using analysis of variance and an equivalence test. Equivalence to placebo was evidenced if the 95% confidence interval lay between -2.6 cm and +2.6 cm. RESULTS: SDLP after levocetirizine was equivalent to placebo on both day 1 (-0.66 cm; +1.12 cm) and day 4 (-0.37 cm; +1.28 cm). In contrast, SDLP after diphenhydramine differed significantly from placebo on both day 1 ( P<0.0001) and day 4 ( P<0.0003). On day 1, the 95% confidence interval of diphenhydramine (+1.85 cm; +3.63 cm) was partially above the upper equivalence limit (+2.6 cm), indicating clinically relevant driving impairment. On day 4, however, the 95% confidence interval of diphenhydramine (+0.74 cm; +2.38 cm) was contained within the acceptance range. CONCLUSION: In contrast to diphenhydramine, driving performance was not significantly affected while using 5 mg levocetirizine once daily.

Detection of visual change: mismatch or rareness?

How do we detect changes in our visual environment? By continuously comparing visual inputs to templates of experiences in the immediate past? Or by determining their rareness, how infrequently a visual event occurred previously? Recent results from event-related potentials have been interpreted in favour of the first hypothesis, as in the case of the auditory mismatch negativity. Here we demonstrate that rareness, rather than mismatch with a template, underlies visual change detection. Such rareness is detected through a dedicated mechanism in human visual cortex about 100 ms after the rare event occurs, reflected in the rareness-related negativity (RRN).