Acute separate and combined effects of cannabinoid and nicotinic receptor agonists on MMN-indexed auditory deviance detection in healthy humans.

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.

Neurocognitive effects of acute choline supplementation in low, medium and high performer healthy volunteers.

Novel pharmacological treatments targeting alpha 7 nicotinic acetylcholine receptor (α7 nAChR) hypofunction in schizophrenia have shown mixed success in ameliorating cognitive impairments associated with this disorder. Choline, a selective agonist at α7 receptors is increased with oral administration of cytidine 5'-diphosphocholine (CDP-choline), the cognitive effects of which were assessed in healthy volunteers. Using the CogState test battery, behavioral performance in schizophrenia-relevant cognitive domains was assessed in 24 male participants following a single low (500mg) and moderate (1000mg) dose of CDP-choline. Relative to placebo, CDP-choline improved processing speed, working memory, verbal learning, verbal memory, and executive function in low baseline performers, while exerting no effects in medium baseline performers, and diminishing cognition in high baseline performers. Dose effects varied with cognitive domain but were evident with both the 500mg and 1000mg doses. These preliminary findings of cognitive enhancement in relatively impaired performers are consistent with the α7 receptor mechanism and support further trials with CDP-choline as a potential pro-cognitive strategy for cognitive impairment in schizophrenia.

CDP-choline: effects of the procholine supplement on sensory gating and executive function in healthy volunteers stratified for low, medium and high P50 suppression.

Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (α7 nAChR), the targeting of which may have treatment potential. Choline is a selective α7 nAChR agonist and the aim of this study was to determine whether cytidine 5'-diphosphocholine (CDP-choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy.

Modulation of auditory deviance detection by acute nicotine is baseline and deviant dependent in healthy nonsmokers: a mismatch negativity study.

OBJECTIVE: Cognitive enhancement resulting from nicotinic acetylcholine receptor stimulation may be evidenced by increased efficiency of the auditory-frontal cortex network of auditory discrimination, which is impaired in schizophrenia, a cognitive disorder associated with excessive tobacco use. Investigating automatic (preattentive) detection of acoustic change with the mismatch negativity (MMN) brain event-related potential in response to nicotine in individuals with varying baseline levels of auditory discrimination may provide useful insight into the cholinergic regulation of this neural network and its potential amelioration with novel nicotinic agents. METHODS: Sixty healthy, non-smoking male volunteers were presented with an 'optimal' multi-feature MMN paradigm in a randomized, placebo controlled double-blind design with 6 mg of nicotine gum. RESULTS: Participants with low, medium, and high baseline amplitudes responded differently to nicotine (vs. placebo), and nicotine response was feature specific. Whereas MMN in individuals with high amplitudes was diminished by nicotine, MMN increased in those with low amplitudes. Nicotine effects were not shown in medium amplitude participants. CONCLUSIONS: These findings provide preliminary support for the role of nicotinic neurotransmission in sensory memory processing of auditory change and suggest that nicotinic receptor modulation can both enhance and diminish change detection, depending on baseline MMN and its eliciting stimulus feature.

Attenuation of mismatch negativity (MMN) and novelty P300 in schizophrenia patients with auditory hallucinations experiencing acute exacerbation of illness.

This study examined measures of early auditory feature analysis, including the mismatch negativity (MMN) and novelty P300 (NP3) in schizophrenia patients (SZ) with persistent auditory hallucinations (AH) during an acute psychotic episode requiring hospitalisation. Neuroelectric activity was recorded in 10 SZ patients and 13 healthy controls (HC) during a passive auditory oddball task including novel environmental sounds. MMN/NP3 amplitudes and latencies were compared between groups and were correlated with trait (PSYRATS) and state measures of AH severity as well as clinical symptom ratings in SZs.SZ patients (vs. HCs) exhibited reduced MMN amplitudes to both rare deviant and novel stimuli, as well as reduced NP3 amplitudes. Additionally, while novelty MMN amplitudes were correlated with measures of hallucinatory trait, NP3 amplitudes were correlated with measures of hallucinatory state. Therefore, in acutely ill SZ patients, individual components of the auditory novelty detection mechanism may be differentially sensitive to varying aspects of AHs.

Baseline dependency of nicotine's sensory gating actions: similarities and differences in low, medium and high P50 suppressors.

Reduced suppression of the P50 auditory event-related potential in schizophrenia patients relative to normal controls is indicative of a sensory gating deficit and is one of the most robust findings reported for functional brain abnormalities in this disorder. However, there is considerable gating variability in patients and controls and there is little understanding as to how inter-individual differences moderate gating responses to drugs and nicotinic agonists in particular, which have shown potential to reverse gating deficits. In this study the effects of acutely administered nicotine (gum, 6 mg) on sensory gating in a paired (S1-S2) auditory stimulus paradigm were investigated in 57 healthy, non-smoking volunteers stratified as low (n = 19), medium (n = 19) and high (n = 19) P50 suppressors on the basis of three separate baseline derived gating indices, P50 ratios, P50 difference scores, and gating difference waveforms. Relative to placebo, nicotine consistently improved gating in low suppressors as stratified with all three gating indices, exerted no effects in medium suppressors and reduced gating in high suppressors. Analysis of individual stimulus (S2, S2) amplitudes showed distinctly different mechanisms of action underlying nicotine effects in individuals with low and high baseline suppression. The results parallel similar findings of baseline-dependency in the gating effects of several antipsychotic drugs in healthy volunteers and support the use of group segmentation as a translational model in novel cognitive drug development for schizophrenia.

Auditory P3 in antidepressant pharmacotherapy treatment responders, non-responders and controls.

Event-related potentials (ERPs), derived from electroencephalographic (EEG) recordings, can index electrocortical activity related to cognitive operations. The fronto-central P3a ERP is involved in involuntary processing of novel auditory information, whereas the parietal P3b indexes controlled attention processing. The amplitude of the auditory P3b has been found to be decreased in major depressive disorder (MDD). However, few studies have examined the relations between the P3b, the related P3a, and antidepressant treatment response. We tested 53 unmedicated individuals (25 females) with MDD, as well as 43 non-depressed controls (23 females) on the novelty oddball task, wherein infrequent deviant (target) and frequent standard (non-target) tones were presented, along with infrequent novel (non-target/distractor) sounds. The P3a and P3b ERPs were assessed to novel and target sounds, respectively, as were their accompanying behavioral performance measures. Depression ratings and the antidepressant response status were assessed following 12 weeks of pharmacotherapy with three different regimens. Antidepressant treatment non-responders had smaller baseline P3a/b amplitudes than responders and healthy controls. Baseline P3b amplitude also weakly predicted the extent of depression rating changes by week 12. Females exhibited larger P3a/b amplitudes than males. With respect to task performance, controls had more target hits than treatment non-responders. ERP measures correlated with clinical changes in males and with behavioral measures in females. These results suggest that greater (or control-like) baseline P3a/b amplitudes are associated with a positive antidepressant response, and that gender differences characterize the P3 and, by extension, basic attentive processes.

Auditory verbal hallucinations in schizophrenia correlate with P50 gating.

OBJECTIVE: While auditory verbal hallucinations (AVHs) are a common symptom of schizophrenia, the underlying mechanisms behind these perceptual anomalies and their effects on auditory processing are not fully understood. Patients suffering from schizophrenia have been shown to exhibit impaired sensory gating of acoustic stimuli, evidenced by a failure to inhibit the auditory P50 scalp recorded middle latency evoked potential response to the second of two paired auditory "clicks" (S1-S2). METHODS: Because abnormal activation of auditory pathways is associated with a general AVH trait of schizophrenia patients, this study correlated the hallucinatory trait subscale of the Psychotic Symptoms Ratings Scale (PSYRATS) scores of 16 actively hallucinating patients with their P50 responses to S1 and S2 as well as sensory gating indices. P50 gating in patients was also compared to twenty one healthy controls. RESULTS: Control S1 amplitudes were significantly greater than those of patients. There was a negative correlation between PSYRATS scores and gating difference score as well as with S1 amplitude, and a positive correlation with gating ratio, indicating the global trait of hallucinating schizophrenia patients may be associated with deficiencies in the processing of auditory stimuli. No significant correlation was found when the same analysis was applied to a state-dependent hallucination ratings scale. SIGNIFICANCE: Results suggest the relationship between auditory hallucinations and auditory processing dysfunction measured by P50 response is more trait than state dependent in schizophrenia.

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.

Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified 'optimal' multi-feature paradigm.

UNLABELLED: The recently developed Optimal-3 multi-feature MMN paradigm, a shortened version of the 'optimal' multi-feature MMN paradigm, allows for the focused recording of the most widely reported MMN deviants (frequency, duration, intensity) within an efficient and time-saving paradigm. The objective of this study was to examine MMN acoustic change detection in schizophrenia (SZ), and elucidate its association with auditory verbal hallucinations (AH), using the Optimal-3. METHODS: MMN to duration, frequency and intensity deviants were recorded in 12 SZ outpatients (SZs) with persistent AHs and 12 matched healthy controls (HC). Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between groups and were correlated with trait (PSYRATS) and state measures of AH severity and Positive and Negative Syndrome Scale (PANSS) ratings in SZs. RESULTS: SZs showed a significantly smaller duration MMN compared to HCs. Furthermore, in SZs attenuated duration MMN amplitudes were correlated with increased PSYRATS scores, as well as increased PANSS positive symptom, hallucination item and general psychoticism ratings, while attenuated intensity MMN amplitudes were correlated with increased PSYRATS scores. CONCLUSIONS: This is the first study to examine MMN in SZ within the modified (Optimal-3) multi-feature MMN paradigm. This study corroborates previous research reporting a robust duration MMN deficit in SZ and supports previous findings suggesting that AHs may contribute to MMN deficits in SZ.

Effects of deviant probability on the 'optimal' multi-feature mismatch negativity (MMN) paradigm.

UNLABELLED: The introduction of the multi-feature 'optimal' mismatch negativity (MMN) paradigm was a significant innovation that allows for the collection of MMNs from five different deviant types in a relatively short period of time. Given the very specific stimulus presentation structure of this paradigm, the deletion of deviants results in an increase in the stimulus probability of each remaining deviant while holding constant the probability of the standard stimulus. The focus of this paper is two-fold: first, to examine the effects of altering deviant probability, but not standard probability, on MMN generation and, secondly, to validate a shorter, 3-stimulus version of the 'optimal' paradigm. METHODS: Twenty-four participants were presented either with the original 5-stimulus 'optimal' multi-feature MMN paradigm (Optimal-5) or a modified, 3-stimulus version containing only duration, frequency and intensity deviants (Optimal-3). MMN amplitudes and latencies to common deviant types were compared between groups. RESULTS: MMN amplitudes elicited by Optimal-3 were significantly smaller than those elicited by Optimal-5 for frequency and intensity deviants. There were no significant differences between MMN amplitudes for duration deviants, nor were there any significant MMN latency differences for any of the three deviant types. CONCLUSIONS: These results support previous suggestions that MMN attenuation following increased deviant presentation probability is due to the development of separate deviant memory traces, not due to a weakening of the standard memory trace. Furthermore, while MMN amplitudes to Optimal-3 were reduced, they were still present; the Optimal-3 paradigm may be a useful tool for eliciting MMNs in populations unable to tolerate long test sessions, such as acute schizophrenia.

Why are you calling me? How study introductions change response patterns.

PURPOSE: Research on survey methodology has demonstrated that seemingly innocuous aspects of a survey's design, such as the order of questions, can produce biased results. The current investigation extends this work by testing whether standard survey introductions alter the observed associations between variables. METHODS: In two experimental studies, we invited Parkinson's disease (PD) patients to participate in a telephone survey of (a) Parkinson's patients, conducted by a regional medical center, or (b) the general population, conducted by a regional university. The survey in Study 1 (n = 156) first assessed life-satisfaction, and subsequently health satisfaction. In Study 2 (n = 99), we reversed the order of the two questions, asking the health questions first. RESULTS: When the introduction focused on Parkinson's disease, we observed an increased correlation between life-satisfaction and a later question about health satisfaction (r = 0.34 vs. 0.63 after general population versus Parkinson's introduction, respectively; Study 1). In Study 2, asking the health questions first resulted in high correlations regardless of the introduction; in addition, judgments of life-satisfaction were lower after the Parkinson's-focused introduction. CONCLUSIONS: When participants were informed prior to the survey that its purpose was to examine well-being in PD, health satisfaction was a much more important component of life-satisfaction, accounting for three times as much variation. We hypothesize that the survey introduction primed participants' health status, resulting in an artificially large correlation with life-satisfaction.

Comparing clinical automated, medical record, and hybrid data sources for diabetes quality measures.

BACKGROUND: Little is known about the relative reliability of medical record and clinical automated data, sources commonly used to assess diabetes quality of care. The agreement between diabetes quality measures constructed from clinical automated versus medical record data sources was compared, and the performance of hybrid measures derived from a combination of the two data sources was examined. METHODS: Medical records were abstracted for 1,032 patients with diabetes who received care from 21 facilities in 4 Veterans Integrated Service Networks. Automated data were obtained from a central Veterans Health Administration diabetes registry containing information on laboratory tests and medication use. RESULTS: Success rates were higher for process measures derived from medical record data than from automated data, but no substantial differences among data sources were found for the intermediate outcome measures. Agreement for measures derived from the medical record compared with automated data was moderate for process measures but high for intermediate outcome measures. Hybrid measures yielded success rates similar to those of medical record-based measures but would have required about 50% fewer chart reviews. CONCLUSIONS: Agreement between medical record and automated data was generally high. Yet even in an integrated health care system with sophisticated information technology, automated data tended to underestimate the success rate in technical process measures for diabetes care and yielded different quartile performance rankings for facilities. Applying hybrid methodology yielded results consistent with the medical record but required less data to come from medical record reviews.