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RationaleThe 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/methodsThis 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.ResultsIncreases 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.ConclusionsThese 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.

Aberrant gamma-band (30-80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on γEP and γPL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20 mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1 ms, 85 dB clicks in 250-0.5 s trains at a frequency of 40 Hz; 0.5 s inter-train interval) was used to assess γEP and γPL. SZ patients had reduced γEP and γPL; memantine enhanced γEP and γPL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for γEP and γPL: greater memantine sensitivity on γEP and γPL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

RationaleElectrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans.ObjectivesThe main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual’s baseline performance.MethodsYoung (18–27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance.ResultsNicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = − 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement.ConclusionsNicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19–23 years old) normal-hearing nonsmokers and elderly (61–80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-d-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30–100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Chronic stress has been shown to have long-term effects on functional hemispheric asymmetries in both humans and non-human species. The short-term effects of acute stress exposure on functional hemispheric asymmetries are less well investigated. It has been suggested that acute stress can affect functional hemispheric asymmetries by modulating inhibitory function of the corpus callosum, the white matter pathway that connects the two hemispheres. On the molecular level, this modulation may be caused by a stress-related increase in cortisol, a major stress hormone. Therefore, it was the aim of the present study to investigate the acute effects of cortisol on functional hemispheric asymmetries. Overall, 60 participants were tested after administration of 20 mg hydrocortisone or a placebo tablet in a cross-over design. Both times, a verbal and an emotional dichotic listening task to assess language and emotional lateralization, as well as a Banich–Belger task to assess interhemispheric integration were applied. Lateralization quotients were determined for both reaction times and correctly identified syllables in both dichotic listening tasks. In the Banich–Belger task, across-field advantages were determined to quantify interhemispheric integration. While we could replicate previously reported findings for these tasks in the placebo session, we could not detect any differences in asymmetry between hydrocortisone and placebo treatment. This partially corroborates the results of a previous study we performed using social stress to induce cortisol increases. This suggests that an increase in cortisol does not influence dichotic listening performance on a behavioral level. As other studies reported an effect of stress hormones on functional hemispheric asymmetries on a neuro-functional level, future research using neuronal imaging methods would be helpful in the characterization of the relation of hemispheric asymmetries and stress hormones.

Rationale Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine ( N -methyl- d -aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT 2A agonist model). Objectives The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design. Materials and methods Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT 2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S -ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation. Results Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S -ketamine intake, and only S -ketamine had a significant impact on the frontal source of MMN. Conclusions The NDMA antagonist model and the 5HT 2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

Rationale Suppression of redundant auditory information and facilitation of deviant, novel, or salient sounds can be assessed with paired-click and oddball tasks, respectively. Electrophysiological correlates of perturbed auditory processing found in these paradigms are likely to be a trait marker or candidate endophenotype for schizophrenia. Objective This is the first study to investigate the effects of the muscarinic M1 antagonist biperiden and the cholinesterase inhibitor rivastigmine on auditory-evoked potentials (AEPs), sensory gating, and mismatch negativity (MMN) in young, healthy volunteers. Results Biperiden increased P50 amplitude and prolonged N100 and P200 latency in the paired-click task but did not affect sensory gating. Rivastigmine was able to reverse the effects of biperiden on N100 and P200 latency. Biperiden increased P50 latency in the novelty oddball task, which was reversed by concurrent administration of rivastigmine. Rivastigmine shortened N100 latency and enhanced P3a amplitude in the novelty oddball paradigm, both of which were reversed by biperiden. Conclusion The muscarinic M1 receptor appears to be involved in preattentive processing of auditory information in the paired-click task. Additional effects of biperiden versus rivastigmine were reversed by a combination treatment, which renders attribution of these findings to muscarinic M1 versus muscarinic M2–M5 or nicotinic receptors much more difficult. It remains to be seen whether the effects of cholinergic drugs on AEPs are specifically related to the abnormalities found in schizophrenia. Alternatively, aberrant auditory processing could also be indicative of a general disturbance in neural functioning shared by several neuropsychiatric disorders and/or neurodegenerative changes seen in aging.

Rationale Although the attention-enhancing effects of nicotine have been behaviorally and neurophysiologically well-documented, its localized functional effects during selective attention are poorly understood. Objectives In this study, we examined the neuronal effects of nicotine during auditory selective attention in healthy human nonsmokers. We hypothesized to observe significant effects of nicotine in attention-associated brain areas, driven by nicotine-induced increases in activity as a function of increasing task demands. Methods A single-blind, prospective, randomized crossover design was used to examine neuronal response associated with a go/no-go task after 7 mg nicotine or placebo patch administration in 20 individuals who underwent functional magnetic resonance imaging at 3T. The task design included two levels of difficulty (ordered vs. random stimuli) and two levels of auditory distraction (silence vs. noise). Results Significant treatment × difficulty × distraction interaction effects on neuronal response were observed in the hippocampus, ventral parietal cortex, and anterior cingulate. In contrast to our hypothesis, U and inverted U-shaped dependencies were observed between the effects of nicotine on response and task demands, depending on the brain area. Conclusions These results suggest that nicotine may differentially affect neuronal response depending on task conditions. These results have important theoretical implications for understanding how cholinergic tone may influence the neurobiology of selective attention.

Rationale and objective Nicotine is known to have enhancing effects on some aspects of attention and cognition. The purpose of the present study was to elucidate the effects of nicotine on pre-attentive change-related cortical activity. Methods Change-related cortical activity in response to an abrupt increase (3 dB) and decrease (6 dB) in sound pressure in a continuous sound was recorded by using magnetoencephalography. Nicotine was administered with a nicotine gum (4 mg of nicotine). Eleven healthy nonsmokers were tested with a double-blind and placebo-controlled design. Effects of nicotine on the main component of the onset response peaking at around 50 ms (P50m) and the main component of the change-related response at around 120 ms (Change-N1m) were investigated. Results Nicotine failed to affect P50m, while it significantly increased the amplitude of Change-N1m evoked by both auditory changes. The magnitude of the amplitude increase was similar among subjects regardless of the magnitude of the baseline response, which resulted in the percent increase of Change-N1m being greater for subjects with Change-N1m of smaller amplitude. Conclusions Since Change-N1m represents a pre-attentive automatic process to encode new auditory events, the present results suggest that nicotine can exert beneficial cognitive effects without a direct impact on attention.