Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia.

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine×nicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia.

Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

Nicotine and the hallucinating brain: effects on mismatch negativity (MMN) in schizophrenia.

Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs.

Interaction of estrogen with central serotonergic mechanisms in human sensory processing: loudness dependence of the auditory evoked potential and mismatch negativity.

Estrogen may be involved in schizophrenia by inhibiting serotonin-1A (5-HT(1A)) receptor function. We examined the effects of estrogen pre-treatment on modulation of loudness dependence of the auditory evoked potential (LDAEP) and mismatch negativity by the 5-HT(1A) receptor partial agonist, buspirone. Using a double-blind, placebo-controlled, repeated-measures design in healthy female volunteers, we observed that buspirone treatment significantly increased LDAEP slope. Estrogen increased LDAEP slope on its own, and a further LDAEP increase by buspirone was not seen after estrogen pre-treatment. Similar results were observed for mismatch negativity, where buspirone caused a small increase of latency, although not amplitude, after placebo but not estrogen pre-treatment, which enhanced mismatch negativity latency on its own. These results are in line with our previous findings on prepulse inhibition showing an inhibitory effect of estrogen on the action of buspirone. Taken together, these data suggest that estrogen may inhibit 5-HT(1A) receptor-mediated disruptions of auditory processing.

Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform.

INTRODUCTION: Cholinergic agonists and, more specifically, nicotine, have been found to enhance a number of cognitive processes. The effect of nicotine on temporal processing is not known. The use of behavioral measures of temporal processing to measure its effect could be confounded by the general effects of nicotine on attention. Mismatch negativity (MMN) has been used as a physiological measure of automatic temporal processing to avoid this potential confound. METHODS: A total of 20 subjects (11 nonsmokers and 9 smokers following 2 hr of abstinence) participated in a two-visit single-blind, placebo-controlled crossover study of the effect of nicotine on MMN indices in response to an interstimulus interval deviant. RESULTS: Nicotine-enhanced MMN amplitudes from baseline recording to postdrug recording greater than did the placebo condition. This enhancement was seen in both nonsmokers and smokers. Nicotine had no significant effect on MMN latency or N100 amplitude or latency. DISCUSSION: This is the first study to demonstrate a nicotine-related enhancement of MMN amplitude to an interstimulus interval duration deviant and confirms our hypothesis that nicotine enhances preattentive temporal processing. Nicotinic agonists may represent a potential therapeutic option for individuals with abnormalities in early sensory or temporal processing related to cholinergic system abnormalities. Methodologically, our paradigm of nicotine administration in abstinent smokers is important because it resulted in both minimal withdrawal symptoms and meaningful data that are not attributable solely to relief of withdrawal.

Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Nicotine effects on mismatch negativity in nonsmoking schizophrenic patients.

BACKGROUND: The goal of the present study is to identify the effect of nicotine on auditory automatic processing, as reflected by mismatch negativity (MMN), in nonsmoking schizophrenic patients. METHODS: Ten nonsmoking schizophrenic patients and 10 healthy volunteers underwent a reference session and 2 test sessions. The test sessions involved administration of a placebo patch and a nicotine skin patch, which were counterbalanced. Nicotine was administered transdermally under controlled dosage. RESULTS: Nicotine administration shortened the MMN latencies (at Fz on nicotine/placebo: 134.8 +/- 5.7/157.6 +/- 6.4 ms) in healthy volunteers. In contrast, there were no significant differences in MMN latencies in schizophrenic patients (169.6 +/- 5.7/165.0 +/- 6.4 ms). CONCLUSION: Nicotine activates and accelerates preattentive and automatic processing in healthy controls, whereas there were no such effects observed in nonsmoking patients. The impaired MMN response to nicotine administration in nonsmoking schizophrenic patients may be attributed to low nicotinic receptor function, implicated in dysregulation of the glutamatergic system.

Brief report: changes in brain function during acute cannabis intoxication: preliminary findings suggest a mechanism for cannabis-induced violence.

BACKGROUND: Recent evidence suggests that cannabis use may be associated with antisocial and violent behaviour, raising the question: What brain mechanisms mediate the disinhibiting effects of cannabis on behaviour? AIMS/HYPOTHESES: To examine whether an electrocortical measure of affective impulsivity, Go/No Go contingent negative variation, is affected by acute cannabis intoxication. METHODS: Slow brain potentials were recorded in a Go/No Go noise avoidance task from five habitual cannabis users before, during and after they smoked a cannabis reefer containing 11 mg D-9-tetrahydrocannabinol. RESULTS: Slow brain potentials developed normally in both Go and No Go conditions before and during cannabis smoking but were severely disrupted 20-40 minutes later, coincident with peak intoxication. Cannabis effects on Go/No Go brain activity resembled those reported to occur in patients with lateral prefrontal cortex lesions. CONCLUSION/IMPLICATIONS: Our findings are preliminary, calling for larger-scale studies, to confirm the present findings and to investigate whether brain responses to cannabis intoxication differentiate those who are predisposed to suffer adverse consequences of cannabis use from those who are not.

Simultaneous recording of eeg and direct current (DC) potential makes it possible to assess functional and metabolic state of nervous tissue.

It has been proposed to assess functional and metabolic state of the brain nervous tissue in terms of bioelectrical parameters. Simultaneous recording of the DC potential level and total slow electrical activity of the nervous tissue was performed in the object of study by nonpolarizable Ag/AgCl electrodes with a DC amplifier. The functional and metabolic state of the brain was determined in terms of enhancement or reduction in the total slow electrical activity and positive or negative shifts in the DC potential level.

Nicotine and sensory memory in Alzheimer's disease: an event-related potential study.

The auditory mismatch negativity (MMN) event-related brain potential (ERP) reflects the storage of information in acoustic sensory memory. Thirteen patients with probable Alzheimer's disease (AD), 6 receiving treatment with the cholinesterase inhibitor (ChEI) tacrine (tetrahydroaminoacridine, THA) and 7 receiving no treatment, were administered 2 mg of nicotine polacrilex and placebo. MMNs were recorded with 1- and 3-s interstimulus intervals pre- and postplacebo/nicotine administration. In nontreated patients, amplitudes were decreased from pre- to postplacebo recordings but remained stable in THA-treated patients. Comparison of pre- and postnicotine MMNs found amplitude increases with nicotine in nontreated but not THA-treated patients. MMN latencies were shortened by nicotine in both treatment groups. These exploratory findings suggest that nicotine-improved strength of acoustic sensory memory traces and speed of acoustic sensory discrimination in AD are differentially affected by chronic ChEI treatment.

Effects of smoking and telic/paratelic dominance on the contingent negative variation (CNV).

Concepts from reversal theory, a general theory of motivation, emotion and action, have recently been shown to be relevant to smoking behavior and smoking cessation. One relevant concept is that of telic and paratelic dominance. Individuals who are paratelic-dominant are playful, spontaneous, and prefer high arousal seeking. Those who are telic-dominant are serious, tend to plan ahead, and prefer low arousal. This led to the hypothesis that smoking might increase the amplitude of the contingent negative variation (CNV) in paratelic-dominant smokers more than in telic-dominant smokers. CNV was obtained using a Go/NoGo reaction time task with a 2 s S1-S2 interval and variable intertrial intervals. S1 indicated whether the subject was to respond to S2 or not. Errors were punished with a burst of white noise. Subjects performed the CNV task three times: after being deprived of smoking for at least 4 h; after sham smoking; and after smoking a cigarette of their own brand. Telic-dominant subjects differed from paratelic-dominant subjects in the relative amplitude of early (1 s) and late (2 s) components of the CNV. Smoking did not differentially affect the dominance groups unless gender was taken into account, and the most striking interactions between smoking and dominance groups were noted for the NoGo trials. As expected, smoking decreased the amplitude of the early component of the NoGo CNV for telic-dominant women, but increased it for paratelic-dominant women; no significant differences were found for the late component. In men, smoking increased the late CNV more for telics than for paratelics, while smoking did not differentially affect the early component.

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.

Effect of peppermint and eucalyptus oil preparations on neurophysiological and experimental algesimetric headache parameters.

The effects of peppermint oil and eucalyptus oil preparations on neurophysiological, psychological and experimental algesimetric parameters were investigated in 32 healthy subjects in a double-blind, placebo-controlled, randomized cross-over design. Four different test preparations were applied to large areas of the forehead and temples using a small sponge and their effect was evaluated by comparing baseline and treatment measure. The combination of peppermint oil, eucalyptus oil and ethanol increased cognitive performance and had a muscle-relaxing and mentally relaxing effect, but had little influence on pain sensitivity. A significant analgesic effect with a reduction in sensitivity to headache was produced by a combination of peppermint oil and ethanol. The essential plant oil preparations often used in empiric medicine can thus be shown by laboratory tests to exert significant effects on mechanisms associated with the pathophysiology of headache.

Cardiovascular, electrocortical, and behavioral effects of nicotine chewing gum.

The cardiovascular, electrocortical, and behavioral effects of orally administered nicotine during rapid information processing were assessed in deprived female smokers. In a pre-post treatment design, 10 subjects received a 4-mg nicotine chewing gum and 10 subjects a placebo. The mental task required the subjects to watch single digits presented in a pseudorandom order on a screen and to press a button whenever the last three digits were either odd or even. The presentation rate decreased after each error and increased after each correct response and was used as the index of performance. Event-related brain potentials (ERP) to each of the three digits of the correctly answered triads were analyzed. The ERPs showed a distinct CNV potential for the second digit only (expectancy) and a P300 response for the third digit only (response decision). The mean EEG power spectrum was computed for each 5-min resting period, set before each trial and at the end of the session. A single administration of 4-mg nicotine chewing gum was followed by heart rate increase, acrodermal vasoconstriction, increase in theta and alpha frequency, decrease in delta power, and increase in the CNV magnitude. However, the chewing gum neither increased performance or reaction time nor decreased any ERP latencies or amplitudes, as has been reported after cigarette smoking.

The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man.

1 The effects of two doses of delta 9THC (2.5 and 10 mg), delivered by paced smoking of herbal cigarettes, on CNV magnitude, subjective mood ratings and heart rate were studied in 20 subjects. 2 There were highly significant interactions between drug dosage and Extraversion and Neuroticism scores, so that the direction and degree of response to the different doses of delta 9THC depended on the personality characteristics of the subjects. 3 The effects of 9 mg delta 9THC and placebo, delivered in herbal cigarettes smoked naturally, on smoking behaviour, subjective mood ratings, measures of autonomic activity and auditory and visual cortical evoked responses were compared in 12 subjects. 4 Smoking behaviour, subjective 'high' rating and elevation of heart rates were the most significant discriminators between drug and placebo. The latency of some of the components of the visual evoked responses was also increased by delta 9THC. 5 There was a significant correlation between the effects of delta 9THC on skin conductance reactivity and the basal (pre-drug) level, reactivity increasing after drug in subjects with low basal reactivity and decreasing in those with high basal levels. 6 Both experiments provided clear evidence of dose-dependent biphasic stimulant and depressant actions of delta 9THC on both subjective and objective measures, and these effects were influenced by the personality and the starting state of the subjects.

The EEG effects of tobacco smoking--a review.

In summary, smoking does produce obvious changes in EEG activity. Human studies have been limited to surface electrodes. These have provided evidence of the alpha, evoked potential, and CNV effects of smoking. Changes in alpha and evoked potential activity have been statistically analyzed across subjects. These analyses indicated statistically significant arousal effects. However, large individual differences in responding were observed but not analyzed. Analysis of individual data in the Ashton, et. al. (1974) study indicated some arousal effects and some sedative effects, depending on the personality characteristics of the individual subject. Differential effects might have been detected in other studies had individual subject data been adequately analyzed. In research with nonhuman subjects, nicotine and tobacco smoke produced cortical arousal and sometimes a biphasic effect of arousal followed by apparent sedation. Behavioral effects accompanied the cortical arousal, including eyelid opening, head movements, and eye movements. During the synchronization phase, crouching, low mobility, and closed eyes occurred. Both the limbic and reticular activating systems seem to be affected by nicotine and smoking with the hippocampus most noticeably affected.

Separate and combined effects of alcohol and tobacco on the amplitude of the contingent negative variation.

To examine the separate and combined effects of alcohol and tobacco smoking on cortical functioning, the amplitude of the contingent negative variation (CNV) was studied during a simple reaction time task in non-smokers, tobacco-deprived smokers and non-deprived smokers in sessions involving administration of four cigarettes and/or 0.65 g/kg ethyl alcohol. Computer analysis indicated that alcohol and combined alcohol + tobacco significantly reduced the CNV amplitude in non-deprived smokers. Two sub-groups of non-smokers were identified, one showing large pre-drug CNV amplitudes and significant alcohol-induced reductions and the other showing small pre-drug amplitudes and no change in CNV amplitude after alcohol. No significant results were observed with alcohol, tobacco or alcohol + tobacco combined in tobacco-deprived smokers. The results are discussed in relation to previously reported studies which have indicated both synergistic and antagonistic interactions between alcohol and tobacco, and suggestions are forwarded regarding the experimental and clinical significance of tobacco-induced enhancement of CNV amplitude reduction by alcohol.

Methadone effects on brain functioning and type A and B CNV shapes.

Twelve male outpatients participating in a methadone maintenance treatment program were evaluated for the effects of acute administration of methadone on brain functioning (contingent negative variation or CNV), attention performance (reaction time and continuous performance test), and psychophysiological activity (heart rate and eye blink rate). Individual differences in response to methadone were assessed by classifying patients into two groups on the basis of basal CNV shapes: Type A (quick rise time) and type B (slow rise time). Methadone produced a pattern of increased electrical brain activity (CNV) and enhanced attention performance in type B patients and elevated heart rate and lowered eye blink rate in type A subjects. Results are interpreted in terms of the distraction-arousal and the eye blink-hedonia hypotheses.