N-methyl-D-aspartate receptor antagonism impairs sensory gating in the auditory cortex in response to speech stimuli.

Deficits in early auditory sensory processing in schizophrenia have been linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction, but the role of NMDARs in aberrant auditory sensory gating (SG) in this disorder is unclear. This study, conducted in 22 healthy humans, examined the acute effects of a subanesthetic dose of the NMDAR antagonist ketamine on SG as measured electrophysiologically by suppression of the P50 event-related potential (ERP) to the second (S2) relative to the first (S1) of two closely paired (500 ms) identical speech stimuli. Ketamine induced impairment in SG indices at sensor (scalp)-level and at source-level in the auditory cortex (as assessed with eLORETA). Together with preliminary evidence of modest positive associations between impaired gating and dissociative symptoms elicited by ketamine, tentatively support a model of NMDAR hypofunction underlying disturbances in auditory SG in schizophrenia.

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.

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.

Craving-induced EEG reactivity in smokers: effects of mood induction, nicotine dependence and gender.

BACKGROUND/AIMS: Cigarette craving is a core symptom of smoking withdrawal, which is more intense and more frequently observed in smokers with depressed mood. Using self-reports and electroencephalographic (EEG) indices of frontal hemispheric asymmetry, which has been shown to be sensitive to mood states, the purpose of this study was to investigate the neural basis of cue-elicited cigarette craving, its variation with experimentally induced depressed mood, and with differences in gender and smoker type. METHODS: Cigarette-cue reactivity was examined in 11 (5 male) regular and 11 (6 male) light smokers in two sessions involving the induction of neutral or depressed mood. RESULTS: Frontal EEG alpha asymmetry changes reflecting left frontal hypoactivation were evident with cigarette-cue exposure, particularly in female smokers. During cigarette-cue exposure, EEG evidenced both decreases and increases in brain state activation, with the latter activational increments also being influenced by depressed mood. Exposure to the cigarette cue, in addition to increasing withdrawal symptoms, increased cravings and negative affect, these latter effects being more evident in female and regular smokers. CONCLUSION: These findings, which appear to provide a physiological basis for 'withdrawal-like' negative affective experiences during craving, are discussed in relation to theories of drug reinforcement and smoking motivation.

EEG correlates of imagery-induced cigarette craving in male and female smokers.

Functional neuroimaging studies of cue-elicited craving in smokers have identified a distributed system of brain activation which includes the frontal cortex. As electroencephalographic (EEG) activity recorded from frontal brain regions indexes emotive functions, which are believed to play a key role in craving processes, this study examined frontal EEG in 20 cigarette smokers (10 male) exposed to imagery scripts containing positive, negative, or neutral affective content with and without descriptions of smoking urges. Urge scripts increased subjective cravings related to both the rewarding and withdrawal-relief properties of smoking, the latter tending to be greater in female smokers, as were self-reports of frustration. The emotional content of scripts did not moderate urges or EEG but urge scripts were found to: a) decrease activity of delta in male smokers and to increase activity of beta, a pattern which has also been seen with acute smoking, and b) increase activity of theta, a response which has also been seen with smoking abstinence. This imagery-elicited neuroelectric profile, appearing to reflect opposing actions of reward and withdrawal, suggests that EEG may be a sensitive tool for probing the multidimensional nature of craving.

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.

Clonidine pre-treatment fails to block acute smoking-induced EEG arousal/mood in cigarette smokers.

Given the arousal eliciting actions of smoking and nicotine, and the contributing role of noradrenaline in brain arousal systems, this study examined the neuroelectric and affective correlates of cigarette smoking following acute pre-treatment with the alpha 2-noradrenergic auto-receptor agonist, clonidine. In a double-blind placebo-controlled crossover design, quantitative electroencephalography (EEG), mood, and smoking withdrawal symptoms were assessed in 12 overnight smoking abstinence smokers, before and after sham and cigarette smoking. Orally administered clonidine (0.1 mg) failed to alter overnight smoking abstinence symptoms or the EEG arousal and mood-elevating response seen with the smoking of a single cigarette. The results are discussed in relation to neural mechanisms underlying the acute reinforcement maintaining nicotine use.

Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic release at the medial prefrontal cortex.

Like primary reinforcers, the anticipation of reward ought to affect neurochemical release in brain regions, such as the medial prefrontal cortex (mPFC), which are associated with appraisal processes. To assess the neurochemical changes associated with anticipation, rats were exposed to the pairing of auditory (60-dB white noise), visual, and olfactory cues with the daily presentation of a palatable snack (Cue Relevant group). Rats of a second group were similarly trained, but for a 2-week period, the snack was no longer provided following cue presentation (Extinction group). In the third condition, the presentation of the snack and cues was uncorrelated (Cue Irrelevant group). Analyses of dialysates collected in vivo from the mPFC revealed that release of corticotropin-releasing hormone (CRH), gastrin-releasing peptide (GRP), and the 5-HT catabolite, 5-hydroxyindole acetic acid (5-HIAA), had increased bilaterally in response to the anticipatory cues, whereas DA release increased only within the right mPFC. In the case of CRH and GRP, these increases were also apparent in the extinction condition, despite the fact that behavioral arousal to the anticipatory cues (increased exploration, rearing, grooming, and vigilance) was only evident in the Cue Relevant condition. In contrast, the elevated DA and 5-HIAA were apparent exclusively in the Cue Relevant condition. Thus, CRH and GRP systems may serve to allocate salience and/or incentive reward value to biologically significant stimuli or reflect the emotional response to the anticipatory stimulus. The activity of DA and 5-HT neurons, in contrast, is more closely aligned with the cognitive appraisal of predictor stimuli.

Differential involvement of amygdaloid CRH system(s) in the salience and valence of the stimuli.

Anxiety is a heterogeneous term encompassing not only state or trait characteristics but also a wide range of pathologies such as generalized anxiety disorders, phobias, panic and obsessive-compulsive disorders, acute stress disorder, and posttraumatic stress disorder. Given that diverse forms of anxiety exist, numerous animal models have been developed, which are considered to be useful in identifying mechanisms underlying anxiety states. Examples of such animal models include paradigms that assess the behavioral response to neurogenic (or painful stimuli) or psychogenic stressors or to cues that had previously been associated with painful stimuli. The present report presents data regarding the impact of stressors on corticotropin-releasing hormone (CRH), and relates these to changes in anxiety-like states. Specifically, we demonstrate that (1) psychogenic stressors influence the in vivo release of CRH at the central nucleus of the amygdala (CeA); (2) although CRH changes within the CeA are exquisitely sensitive to stressors, they are also elicited by positive stimuli; and (3) while treatment with diazepam attenuates behavioral signs of anxiety, the CRH release associated with a stressor is unaffected by the treatment. The position is offered that although release of CRH within the CeA is increased under stressful conditions, it is not a necessary condition for the consequent behavioral expression of anxiety-like reactions, at least not in minimally threatening situations. We suggest that the CRH responses at the CeA may be involved in a preparatory capacity and, as such, may accompany a range of emotionally significant stimuli, be they appetitive or aversive.

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.

Effects of nicotine on electroencephalography and affect in adolescent females with major depressive disorder: a pilot study.

BACKGROUND: Given that smoking is typically initiated during adolescence, and that this period in brain development seems to be uniquely sensitive to nicotine, depressed youth may be most susceptible to the neuromodulatory and mood-altering effects of nicotine. Electroencephalographic (EEG) studies suggest that individuals with major depressive disorder (MDD) exhibit left frontal lobe hypoactivation (indexed by increased EEG alpha), a region implicated in positive affect regulation, as well as right parietal hypoactivation. Smoking/nicotine abstinence has been associated with increased left frontal and right parietal alpha activity (reduced activation), which has been correlated with increased depression ratings; nicotine administration seems to normalize this depression-associated asymmetry. OBJECTIVES: This pilot study investigated whether acute nicotine administration in adolescent female smokers with MDD would alter resting EEG activity and affect. METHODS: Subjective mood ratings and EEG recordings were acquired before and 2 hours after administering a transdermal placebo or nicotine (21 mg) patch to 8 adolescent female smokers with MDD. RESULTS: Nicotine induced a modest increase in alpha1 amplitude in the right hemisphere and simultaneously decreased left-favoring alpha1 amplitude asymmetry. It also attenuated left alpha1 and alpha2 amplitude in the central region. Consistent with nicotine's stimulatory action, nicotine decreased theta amplitude in the right parietal region. No accompanying mood alterations were found, although smoking withdrawal and craving as well as physical symptom scores were reduced with nicotine. CONCLUSIONS: The results of this pilot study, the first to examine the electrocortical effects of nicotine in depressed adolescents, indicate that nicotine modulates EEG asymmetry measures, laying the stage for further research regarding the role of nicotine on affective neurocircuitry in this population.

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.

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

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

Acute nicotine fails to alter event-related potential or behavioral performance indices of auditory distraction in cigarette smokers.

Behavioral studies have shown that nicotine enhances performance in sustained attention tasks, but they have not shown convincing support for the effects of nicotine on tasks requiring selective attention or attentional control under conditions of distraction. We investigated distractibility in 14 smokers (7 females) with event-related brain potentials (ERPs) and behavioral performance measures extracted from an auditory discrimination task requiring a choice reaction time response to short- and long-duration tones, both with and without embedded deviants. Nicotine gum (4 mg), administered in a randomized, double-blind, placebo-controlled crossover design, failed to counter deviant-elicited behavioral distraction (i.e., slower reaction times and increased response errors), and it did not influence the distracter-elicited mismatch negativity, the P300a, or the reorienting negativity ERP components reflecting acoustic change detection, involuntary attentional switching, and attentional reorienting, respectively. Results are discussed in relation to a stimulus-filter model of smoking and in relation to future research directions.

Anxiety in rats selectively bred for Fast and Slow kindling rates: situation-specific outcomes.

Rats selectively bred for amygdala excitability, realized by fast or slow kindling epileptogenesis, were previously reported to exhibit differential levels of anxiety. Although the Slow kindling rats generally appeared more anxious in several behavioral tests, under certain test conditions the Fast kindling rats displayed greater anxiety or stressor reactivity. The present investigation confirmed that in a test of anxiety comprising suppression of consumption of a palatable snack in an unfamiliar environment, the Slow kindling rats exhibited greater anxiety and that this effect was attenuated by diazepam. Likewise, the acoustic startle response was greater in the Slow kindling rats. However, the fear-potentiated startle response was more pronounced in Fast kindling rats, particularly among females, irrespective of whether the test parameters elicited moderate or high startle amplitudes. The elevated startle in the Slow rats, and the fear potentiated startle in the Fast rats, were attenuated by diazepam. These data indicate the need to differentiate subtypes of anxiety in animal models, and raise the issue that anxiety elicited by specific environmental triggers may interact with genetically determined trait characteristics.