An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine.

BACKGROUND: Cognitive operations including pre-attentive sensory processing are markedly impaired in patients with schizophrenia (SCZ) but evidence significant interindividual heterogeneity, which moderates treatment response with nicotinic acetylcholine receptor (nAChR) agonists. Previous studies in healthy volunteers have shown baseline-dependency effects of the α7 nAChR agonist cytidine 5'-diphosphocholine (CDP-choline) administered alone and in combination with a nicotinic allosteric modulator (galantamine) on auditory deviance detection measured with the mismatch negativity (MMN) event-related potential (ERP). AIM: The objective of this pilot study was to assess the acute effect of this combined α7 nAChR-targeted treatment (CDP-choline/galantamine) on speech MMN in patients with SCZ (N = 24) stratified by baseline MMN responses into low, medium, and high baseline auditory deviance detection subgroups. METHODS: Patients with a stable diagnosis of SCZ attended two randomized, double-blind, placebo-controlled and counter-balanced testing sessions where they received a placebo or a CDP-choline (500 mg) and galantamine (16 mg) treatment. MMN ERPs were recorded during the presentation of a fast multi-feature speech MMN paradigm including five speech deviants. Clinical measures were acquired before and after treatment administration. RESULTS: While no main treatment effect was observed, CDP-choline/galantamine significantly increased MMN amplitudes to frequency, duration, and vowel speech deviants in low group individuals. Individuals with higher positive and negative symptom scale negative, general, and total scores expressed the greatest MMN amplitude improvement following CDP-choline/galantamine. CONCLUSIONS: These baseline-dependent nicotinic effects on early auditory information processing warrant different dosage and repeated administration assessments in patients with low baseline deviance detection levels.

N-methyl-d-aspartate receptor antagonism modulates P300 event-related potentials and associated activity in salience and central executive networks.

Impairments in auditory information processing in schizophrenia as indexed electrophysiologically by P300 deficits during novelty (P3a) and target (P3b) processing are linked to N -methyl- D -aspartate receptor (NMDAR) dysfunction. This study in 14 healthy volunteers examined the effects of a subanesthetic dose of the NMDAR antagonist ketamine on P300 and their relationship to psychomimetic symptoms and cortical source activity (with eLORETA). Ketamine reduced early (e- P3a) and late (l-P3a) novelty P300 at sensor (scalp)-level and at source-level in the salience network. Increases in dissociation symptoms were negatively correlated with ketamine-induced P3b changes, at sensor-level and source-level, in both salience and central executive networks. These P3a alterations during novelty processing, and the symptom-related P3b changes during target processing support a model of NMDAR hypofunction underlying disrupted auditory attention in schizophrenia.

Resting-state functional EEG connectivity in salience and default mode networks and their relationship to dissociative symptoms during NMDA receptor antagonism.

N-methyl-d-aspartate receptor (NMDAR) antagonists administered to healthy humans results in schizophrenia-like symptoms, which are thought in part to be related to glutamatergically altered electrophysiological connectivity in large-scale intrinsic functional brain networks. Here, we examine resting-state source electroencephalographic (EEG) connectivity within and between the default mode (DMN: for self-related cognitive activity) and salience networks (SN: for detection of salient stimuli in internal and external environments) in 21 healthy volunteers administered a subanesthetic dose of the dissociative anesthetic and NMDAR antagonist, ketamine. In addition to provoking symptoms of dissociation, which are thought to originate from an altered sense of self that is common to schizophrenia, ketamine induces frequency-dependent increases and decreases in connectivity within and between DMN and SN. These altered interactive network couplings together with emergent dissociative symptoms tentatively support an NMDAR-hypofunction hypothesis of disturbed electrophysiologic connectivity in schizophrenia.

CDP-choline and galantamine, a personalized α7 nicotinic acetylcholine receptor targeted treatment for the modulation of speech MMN indexed deviance detection in healthy volunteers: a pilot study.

RATIONALE: The combination of CDP-choline, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, with galantamine, a positive allosteric modulator of nAChRs, is believed to counter the fast desensitization rate of the α7 nAChRs and may be of interest for schizophrenia (SCZ) patients. Beyond the positive and negative clinical symptoms, deficits in early auditory prediction-error processes are also observed in SCZ. Regularity violations activate these mechanisms that are indexed by electroencephalography-derived mismatch negativity (MMN) event-related potentials (ERPs) in response to auditory deviance. OBJECTIVES/METHODS: This pilot study in thirty-three healthy humans assessed the effects of an optimized α7 nAChR strategy combining CDP-choline (500 mg) with galantamine (16 mg) on speech-elicited MMN amplitude and latency measures. The randomized, double-blinded, placebo-controlled, and counterbalanced design with a baseline stratification method allowed for assessment of individual response differences. RESULTS: Increases in MMN generation mediated by the acute CDP-choline/galantamine treatment in individuals with low baseline MMN amplitude for frequency, intensity, duration, and vowel deviants were revealed. CONCLUSIONS: These results, observed primarily at temporal recording sites overlying the auditory cortex, implicate α7 nAChRs in the enhancement of speech deviance detection and warrant further examination with respect to dysfunctional auditory deviance processing in individuals with SCZ.

Change in the Neural Response to Auditory Deviance Following Cognitive Therapy for Hallucinations in Patients With Schizophrenia.

Adjunctive psychotherapeutic approaches recommended for patients with schizophrenia (SZ) who are fully or partially resistant to pharmacotherapy have rarely utilized biomarkers to enhance the understanding of treatment-effective mechanisms. As SZ patients with persistent auditory verbal hallucinations (AVH) frequently evidence reduced neural responsiveness to external auditory stimulation, which may impact cognitive and functional outcomes, this study examined the effects of cognitive behavioral therapy for voices (CBTv) on clinical and AVH symptoms and the sensory processing of auditory deviants as measured with the electroencephalographically derived mismatch negativity (MMN) response. Twenty-four patients with SZ and AVH were randomly assigned to group CBTv treatment or a treatment as usual (TAU) condition. Patients in the group CBTv condition received treatment for 5 months while the matched control patients received TAU for the same period, followed by 5 months of group CBTv. Assessments were conducted at baseline and at the end of treatment. Although not showing consistent changes in the frequency of AVHs, CBTv (vs. TAU) improved patients' appraisal (p = 0.001) of and behavioral/emotional responses to AVHs, and increased both MMN generation (p = 0.001) and auditory cortex current density (p = 0.002) in response to tone pitch deviants. Improvements in AVH symptoms were correlated with change in pitch deviant MMN and current density in left primary auditory cortex. These findings of improved auditory information processing and symptom-response attributable to CBTv suggest potential clinical and functional benefits of psychotherapeutical approaches for patients with persistent AVHs.

NMDA Receptor Antagonist Effects on Speech-Related Mismatch Negativity and Its Underlying Oscillatory and Source Activity in Healthy Humans.

Background: Previous studies in schizophrenia have consistently shown that deficits in the generation of the auditory mismatch negativity (MMN) - a pre-attentive, event-related potential (ERP) typically elicited by changes to simple sound features - are linked to N-methyl-D-aspartate (NMDA) receptor hypofunction. Concomitant with extensive language dysfunction in schizophrenia, patients also exhibit MMN deficits to changes in speech but their relationship to NMDA-mediated neurotransmission is not clear. Accordingly, our study aimed to investigate speech MMNs in healthy humans and their underlying electrophysiological mechanisms in response to NMDA antagonist treatment. We also evaluated the relationship between baseline MMN/electrocortical activity and emergent schizophrenia-like symptoms associated with NMDA receptor blockade. Methods: In a sample of 18 healthy volunteers, a multi-feature Finnish language paradigm incorporating changes in syllables, vowels and consonant stimuli was used to assess the acute effects of the NMDA receptor antagonist ketamine and placebo on the MMN. Further, measures of underlying neural activity, including evoked theta power, theta phase locking and source-localized current density in cortical regions of interest were assessed. Subjective symptoms were assessed with the Clinician Administered Dissociative States Scale (CADSS). Results: Participants exhibited significant ketamine-induced increases in psychosis-like symptoms and depending on temporal or frontal recording region, co-occurred with reductions in MMN generation in response to syllable frequency/intensity, vowel duration, across vowel and consonant deviants. MMN attenuation was associated with decreases in evoked theta power, theta phase locking and diminished current density in auditory and inferior frontal (language-related cortical) regions. Baseline (placebo) MMN and underlying electrophysiological features associated with the processing of changes in syllable intensity correlated with the degree of psychotomimetic response to ketamine. Conclusion: Ketamine-induced impairments in healthy human speech MMNs and their underlying electrocortical mechanisms closely resemble those observed in schizophrenia and support a model of dysfunctional NMDA receptor-mediated neurotransmission of language processing deficits in schizophrenia. HIGHLIGHTS: -Neural effects of NMDA receptor blockade on speech processing were assessed in a ketamine model.-Ketamine reduced MMN, theta power, theta phase locking factor and regional cortical current density.-Psychosis-like symptoms induced by ketamine were related to baseline (placebo) neural measures of speech processing.

Combining CDP-choline and galantamine: Effects of a selective α7 nicotinic acetylcholine receptor agonist strategy on P50 sensory gating of speech sounds in healthy volunteers.

BACKGROUND: Schizophrenia (SCZ) patients and relatives have deficits in early cortical sensory gating (SG) typically measured by suppression of electroencephalography-derived P50 event-related potentials (ERPs) in a conditioning-testing (S1-S2) paradigm. Associated with alpha 7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction and shown to be improved with nicotine and α7 nAChR agonists, SG has recently been shown to be improved in low P50 suppressing SCZ patients following acute CDP-choline treatment. AIMS: This pilot study in healthy humans assessed the SG effects of an α7 nAChR strategy combining CDP-choline with galantamine, a positive allosteric modulator (PAM) of nAChRs, aimed at increasing and prolonging nicotinic receptor activity. METHODS: The combined effect of CDP-choline (500 mg) and galantamine (16 mg) on speech P50 gating indices rP50 (S2/S1) and dP50 (S1-S2) was examined in 30 healthy participants stratified into low and high baseline P50 suppressors in a randomized, double-blind, placebo-controlled and counterbalanced design. RESULTS: In low suppressors, CDP-choline/galantamine (vs. placebo) improved rP50 and dP50 gating, and reduced S2P50 amplitudes. No P50 gating effects were observed in high suppressors; however, CDP-choline/galantamine (vs. placebo) increased their S2P50 amplitudes. CONCLUSION: Findings from this pilot study with CDP-choline/galantamine in a healthy, SCZ-like surrogate deficient gating sample are consistent with the association of α7 nAChR mechanisms in SG impairment in SCZ and support further research trials with CDP-choline and galantamine targeting sensory processes.

Combining CDP-choline and galantamine, an optimized α7 nicotinic strategy, to ameliorate sensory gating to speech stimuli in schizophrenia.

Neural α7 nicotinic acetylcholine receptor (nAChR) expression and functioning deficits have been extensively associated with cognitive and early sensory gating (SG) impairments in schizophrenia (SCZ) patients and their relatives. SG, the suppression of irrelevant and redundant stimuli, is measured in a conditioning-testing (S1-S2) paradigm eliciting electroencephalography-derived P50 event-related potentials (ERPs), the S2 amplitudes of which are typically suppressed relative to S1. Despite extensive reports of nicotine-related improvements and several decades of research, an efficient nicotinic treatment has yet to be approved for SCZ. Following reports of SG improvements in low P50 suppressing SCZ patients and healthy participants with the α7 agonist, CDP-choline, this pilot study examined the combined modulatory effect of CDP-choline (500 mg) and galantamine (16 mg), a nAChR positive allosteric modulator and acetylcholinesterase inhibitor, on SG to speech stimuli in twenty-four SCZ patients in a randomized, double-blind and placebo-controlled design. As expected, in low P50 suppressors CDP-choline/galantamine (vs. Placebo) improved rP50 and dP50 scores by increasing inhibitory mechanisms as reflected by S2P50 amplitude reductions. Results also suggest a moderating role for auditory verbal hallucinations in treatment response. These preliminary findings provide supportive evidence for the involvement of α7 nAChR activity in speech gating in SCZ and support additional trials, examining different dose combinations and repeated doses of this optimized and personalized targeted α7 cholinergic treatment for SG dysfunction in subgroups of SCZ patients.

Impairments of emotional face processing in schizophrenia patients: Evidence from P100, N170 and P300 ERP components in a sample of auditory hallucinators.

Patients with schizophrenia show impaired face and emotional expression processing that may be due to early perceptual deficits or late impairments in higher-order emotional facial recognition. This study examined event-related potentials (ERPs) in 23 patients with schizophrenia who experience auditory hallucinations and 19 healthy controls. EEG activity was recorded from 32 scalp sites positioned according to the 10-10 placement system. Linked left and right electrodes at the mastoids served as the reference. The P100, N170 and P300 were measured during an emotional facial identification task, which included neutral, joyful, sad, angry and fearful facial expressions and non-face stimuli (chairs). P100 was measured at O1/2 and P7/8. N170 was measured at P7/8. P300 was measured at Pz. Patients with schizophrenia were slower at identifying all facial expressions, including neutral ones. They also showed less positive P100 amplitude to sad, angry and fearful facial expressions. N170 amplitudes were smaller in patients in response to neutral, joyful, sad, angry, and fearful facial expression. Patients showed less positive P300 mean amplitudes to all facial expressions, including neutral ones. Within-group comparisons showed that patients exhibited a different pattern of ERP modulation across facial expressions than controls for P100 and N170, but not for P300. Our findings are compatible with the idea that behavioural and electrophysiological face-processing deficits in schizophrenia arise from early-stage deficits in visual processing.

An electrophysiological investigation of attentional bias in a PTSD population.

OBJECTIVE: Evidence relying on probe detection tasks suggests that anxious individuals exhibit an enhanced selective attentional bias toward emotional or threating stimuli, characterized by attentional vigilance or avoidance of threat. METHOD: Amplitude of P100 and P300 event-related potentials and behavioral measures of target detection were assessed during presentation of a dot-probe task in 18 posttraumatic stress disorder patients and 18 healthy controls to elucidate the effects of attentional bias toward threatening facial expressions. RESULTS: Perceptual (P100) processing of threat-face pairs revealed no evidence of attentional bias in posttraumatic stress disorder (PTSD) patients. PTSD patients exhibited larger P100 and P300 amplitude to probes replacing neutral rather than angry faces, indicating an increased allocation of early perceptual and later strategic processing away from anger-related stimuli. CONCLUSION: The present study provided no support for facilitated engagement in this sample of patients. Possible interpretations of the results related to differential processing of target probes replacing angry-neutral face pairs are discussed. (PsycINFO Database Record

Effects of Ketamine on Resting-State EEG Activity and Their Relationship to Perceptual/Dissociative Symptoms in Healthy Humans.

N-methyl-D-aspartate (NMDA) receptor antagonists administered to healthy humans results in schizophrenia-like symptoms, which preclinical research suggests are due to glutamatergically altered brain oscillations. Here, we examined resting-state electroencephalographic activity in 21 healthy volunteers assessed in a placebo-controlled, double-blind, randomized study involving administration of either a saline infusion or a sub-anesthetic dose of ketamine, an NMDA receptor antagonist. Frequency-specific current source density (CSD) was assessed at sensor-level and source-level using eLORETA within regions of interest of a triple network model of schizophrenia (this model posits a dysfunctional switching between large-scale Default Mode and Central Executive networks by the monitor-controlling Salience Network). These CSDs were measured in each session along with subjective symptoms as indexed with the Clinician Administered Dissociative States Scale. Ketamine-induced CSD reductions in slow (delta/theta and alpha) and increases in fast (gamma) frequencies at scalp electrode sites were paralleled by frequency-specific CSD changes in the Default Mode, Central Executive, and Salience networks. Subjective symptoms scores were increased with ketamine and ratings of depersonalization in particular were associated with alpha CSD reductions in general and in specific regions of interest in each of the three networks. These results tentatively support the hypothesis that pathological brain oscillations associated with hypofunctional NMDA receptor activity may contribute to the emergence of the perceptual/dissociate symptoms of schizophrenia.

The moderating influence of nicotine and smoking on resting-state mood and EEG changes in remitted depressed patients during tryptophan depletion.

Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood.

Nicotine, Auditory Sensory Memory, and sustained Attention in a Human Ketamine Model of Schizophrenia: Moderating Influence of a Hallucinatory Trait.

BACKGROUND: The procognitive actions of the nicotinic acetylcholine receptor (nAChR) agonist nicotine are believed, in part, to motivate the excessive cigarette smoking in schizophrenia, a disorder associated with deficits in multiple cognitive domains, including low-level auditory sensory processes and higher-order attention-dependent operations. OBJECTIVES: As N-methyl-d-aspartate receptor (NMDAR) hypofunction has been shown to contribute to these cognitive impairments, the primary aims of this healthy volunteer study were to: (a) to shed light on the separate and interactive roles of nAChR and NMDAR systems in the modulation of auditory sensory memory (and sustained attention), as indexed by the auditory event-related brain potential - mismatch negativity (MMN), and (b) to examine how these effects are moderated by a predisposition to auditory hallucinations/delusions (HD). METHODS: In a randomized, double-blind, placebo-controlled design involving a low intravenous dose of ketamine (0.04 mg/kg) and a 4 mg dose of nicotine gum, MMN, and performance on a rapid visual information processing (RVIP) task of sustained attention were examined in 24 healthy controls psychometrically stratified as being lower (L-HD, n = 12) or higher (H-HD) for HD propensity. RESULTS: Ketamine significantly slowed MMN, and reduced MMN in H-HD, with amplitude attenuation being blocked by the co-administration of nicotine. Nicotine significantly enhanced response speed [reaction time (RT)] and accuracy (increased % hits and d' and reduced false alarms) on the RVIP, with improved performance accuracy being prevented when nicotine was administered with ketamine. Both % hits and d', as well as RT were poorer in H-HD (vs. L-HD) and while hit rate and d' was increased by nicotine in H-HD, RT was slowed by ketamine in L-HD. CONCLUSIONS: Nicotine alleviated ketamine-induced sensory memory impairment and improved attention, particularly in individuals prone to HD.

Neural expression of nicotine's antidepressant properties during tryptophan depletion: an EEG study in healthy volunteers at risk for depression.

Nicotine amelioration of serotonergically mediated mood dysregulation may contribute to the comorbidity between cigarette smoking and depression, a disorder which is associated with aberrant activation and hemispheric asymmetry in frontal and posterior cortical regions. This randomized, double-blind study in 20 healthy volunteers with a positive family history of depression examined the effects of transdermal nicotine on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). Increased self-ratings of depressed mood and elevation in left frontal high alpha power (decreased activation) were evidenced with ATD (vs. balanced mixture) in participants treated with the placebo but not the nicotine treated group. Nicotine alone increased vigor and posterior high alpha bilaterally, and during ATD it prevented the reduction in left frontal high alpha that was evident in the placebo patch group. These findings indicate that in depression prone individuals, nicotine acts to stabilize the mood lowering and associated frontal functional asymmetry elicited by an acute decrease in brain serotonin.

Acute tryptophan depletion effects on the vertex and late positive potentials to emotional faces in individuals with a family history of depression.

BACKGROUND: Depression, which is associated with dysfunctional serotonin (5-HT) activity, may be characterized by impaired emotional information processing. This study assessed the effects of acute tryptophan depletion (TRP-), which transiently lowers CNS 5-HT, on the emotion-sensitive vertex positive potential (VPP) and late positive potential (LPP) event-related potentials (ERPs) and mood in individuals with a family history of depression. The VPP and LPP are thought to index the early and later stages of motivated attentional processing, respectively. METHOD: Within a double-blind balanced design, ERPs were acquired in 18 individuals with a family history of depression (12 females) after TRP- and TRP+ (balanced) treatment while participants were presented with facial expressions (neutral, as well as sad, joy and surprise at 50 and 100% intensity) and responded to surprised faces. RESULTS: TRP- increased total mood disturbance and maintained depression scores. The VPP and LPP were larger to intense versus mild expressions. Enhanced processing of emotional versus neutral faces, as indexed by the VPP, was primarily evident with TRP-. Speeded and enhanced processing of intensely joyful versus mildly sad faces was found with TRP- (VPP indexed). Compared with TRP+, TRP also increased the VPP to mildly joyful faces. CONCLUSION: Transient 5-HT decreases in individuals with a family history of depression induce subtle changes in early stages of motivated emotional processing, though not in later ones.

Neural effects of acute nicotinic treatment on visual spatial attention in non-smokers.

Enhanced cortical cholinergic signaling associated with nicotinic acetylcholine receptor (nAChR) stimulation has been linked with pro-cognitive actions in a variety of performance domains, including attentional tasks. Improvements in stimulus selection with the nAChR agonist nicotine have been reported but its effects on visual spatial selective attention are unclear. Employing a double-blind, placebo-controlled design, this study examined the acute actions of nicotine (6 mg) in 24 non-smokers performing a visual search task of spatial attention that was probed with behavioral performance measures and the N2pc component of the event-related potentials (ERPs), which served as a neural index of spatial attentional selection. Nicotine did not affect behavioral performance indices. In high symptomatic subjects (as indexed by greater increases in heart rate post-administration), nicotine was associated with an N2pc amplitude enhancement while in low symptomatic individuals it was associated with an N2pc difference amplitude decrease. Nicotine modulation of the ERP marker of spatial attentional selection corroborates in general the attentional effects of nAChR agonists and extends these properties to include altered selective mechanisms during visual spatial processing.

Separate and combined effects of low dose ketamine and nicotine on behavioural and neural correlates of sustained attention.

Given the cognitive-promoting properties of the nicotinic acetylcholinergic receptor (nAChR) agonist, nicotine, the increased prevalence of smoke-inhaled nicotine in schizophrenia has been interpreted as an attempt to self-correct cognitive deficits, which have been particularly pronounced in the attentional domain. As glutamatergic abnormalities have been implicated in these attentional deficiencies, this study attempted to shed light on the separate and interactive roles of the N-methyl-d-aspartate receptor (NMDAR) and nAChR systems in the modulation of attention by investigating, in healthy volunteers, the separate and combined effects of nicotine and the NMDAR antagonist ketamine on neural and behavioural responses in a sustained attention task. In a randomized, double-blind, placebo controlled study, performance and the P300 event-related brain potential (ERP) in a visual information processing (RVIP) task were examined in 20 smokers and 20 non-smokers (both male and female). Assessment involved intravenous injection of a low subperceptual bolus dose (.04mg/kg) of ketamine or placebo, which was accompanied by acute treatment with nicotine (4mg) or placebo gum. Nicotine-enhanced attentional processing was most evident in nonsmokers, with both performance accuracy and P300 amplitude measures. Ketamine's detrimental effects on these behavioural and electrophysiologic measures were negatively moderated by acute nicotine, the synergistic effects being expressed differently in smokers and nonsmokers. These findings support the view that acute alterations and individual differences in nAChR function can moderate even subtle glutamatergic-driven cognitive deficiencies in schizophrenia and can be important therapeutic targets for treating cognitive impairments in schizophrenia.

Electrophysiological evidence of nicotine's distracter-filtering properties in non-smokers.

Nicotine-enhanced attentional functions are purported to underlie improvements in behavioral performance in cognitive tasks but it is unclear as to whether these effects involve selective attention or attentional control under conditions of distraction. Behavioral and event-related potential measures were used to examine the effects of nicotine on distractibility in 21 non-smokers who were instructed to ignore task-irrelevant auditory stimuli while they performed a visual discrimination task. In a randomized, double-blind, placebo-controlled cross-over design, nicotine gum (6 mg) shortened overall reaction times but failed to prevent increased response slowing and errors caused by deviant sounds. Relative to placebo, nicotine did not modulate the early pre-attentive detection of deviants as reflected in the mismatch negativity but it attenuated the amplitude of the deviant-elicited P3a, an event-related potential component indexing the involuntary shifting of attention. Nicotine also enhanced attentional re-focusing back on to task-relevant stimuli following distraction as evidenced by an increased amplitude of the re-orienting negativity. These findings and the behavioral-electrophysiological dissociation seen with nicotine are discussed in relation to theories of attention and smoking motivation.

Electrocortical effects of acute tryptophan depletion on emotive facial processing in depression-prone individuals.

This study assessed the effects of acute tryptophan depletion (ATD), which transiently lowers CNS 5-HT, on electrocortical responses to facial expression processing in individuals with a family history of depression (FH+). Electroencephalograph (EEG)-derived event-related potentials (ERPs) were acquired from 18 FH+ individuals during a facial expression recognition task (neutral and sad, joy and surprise at 50% and 100% intensities). Both early positive (P1 and P2) and the face-specific N170 ERP components were differentially altered by emotional intensity and valence. Increased depression, confusion and total mood disturbance scores, and decreased calmness, were observed with ATD (versus placebo). ATD was also associated with enhanced P1 and P2 amplitudes for sad versus joyful expressions. The N170 was not modulated by treatment, but was affected by emotive valence. Therefore, ATD enhanced ERP-indexed early processing of sad facial expressions, and altered the processing of positive ones, in FH+ individuals.

Light up and see: enhancement of the visual mismatch negativity (vMMN) by nicotine.

Both smoking and nicotine can facilitate cognitive efficiency in humans, however the exact mechanism underlying this improvement in cognitive performance is unclear. Nicotine-related improvements in visual task performance may stem from facilitation of the identification and encoding of rare deviant stimuli at early sensory levels. Visual processes at these early levels are thought to be indexed by the visual mismatch negativity (vMMN), an event-related potential (ERP) measure of pre-conscious deviant detection. In order to contribute to our understanding of the neural mechanisms underlying nicotinic modulated cognition, the current study investigated the acute effects of nicotine on vMMN in a non-smoking sample. Twenty-seven volunteers (7 males, 20 females) were treated with nicotine gum (6 mg) in a double-blind randomized, placebo-controlled repeated measures design. ERPs (vMMN; visual N100 and P200) and motor indices of performance were extracted from an intermodal task, requiring participants to attend selectively to auditory targets presented within concurrent, non-overlapping oddball sequences of visual standard and deviant stimuli. Behavioural performance was unaffected by nicotine, however nicotine was found to enhance vMMN and P200 amplitude. The findings are discussed in relation to attentional and neurobiological theories of nicotine dependence and of cognition in general.