Dhrasti Shah

Effects of acute nicotine on event-related potential and performance indices of auditory distraction in nonsmokers.

INTRODUCTION Although nicotine has been purported to enhance attentional processes, this has been evidenced mostly in tasks of sustained attention, and its effects on selective attention and attentional control under conditions of distraction are less convincing. METHODS This study investigated the effects of nicotine on distractibility in 21 (11 males) nonsmokers with event-related potentials (ERPs) and behavioral performance measures extracted from an auditory discrimination task requiring a choice reaction time response to short- and long-duration tones, with and without imbedded deviants. Administered in a randomized, double-blind, placebo-controlled crossover design, nicotine gum (6 mg) failed to counter deviant-elicited behavioral distraction characterized by longer reaction times and increased response errors. RESULTS Of the deviant-elicited ERP components, nicotine did not alter the P3a-indexed attentional switching to the deviant, but in females, it tended to diminish the automatic processing of the deviant as shown by a smaller mismatch negativity component, and it attenuated attentional reorienting following deviant-elicited distraction, as reflected by a reduced reorienting negativity ERP component. DISCUSSION Results are discussed in relation to attentional models of nicotine and with respect to future research directions.

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.

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. Ketamines 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.

Nicotine and Attention: Event-Related Potential Investigations in Nonsmokers

Research into the effects of nicotine and smoking on cognition has largely confirmed the subjective reports of smoking in smokers on mental functions, showing smoking abstinence to disrupt and smoking/nicotine to restore cognitive functioning. Evidence of performance improvements in nonsmokers has provided partial support for the absolute effects of nicotine on cognitive processes, which are independent of withdrawal relief, but the mechanisms underlying its pro-cognitive properties still remain elusive. The attentional facilitation frequently reported with smoking/nicotine may be indirectly related to its diffuse arousal-enhancing actions, as evidenced by electroencephalographic (EEG) fast frequency power increments, or it may reflect nicotines direct modulating effects on specific neural processes governing stimulus encoding, selection and rejection. Event-related potential (ERP) components extracted during the performance of cognitive tasks have proven to be sensitive to early pre-attentive and later attention-dependent processes that are not otherwise reflected in behavioral probes. To date, the majority of ERP studies have been conducted with smokers using passive non-task paradigms or relatively non-demanding “oddball” tasks. This paper will emphasize our recent ERP investigations with acute nicotine polacrilex (6 mg) administered to nonsmokers, and with a battery of ERP and behavioral performance paradigms focusing on intra- and inter-modal selective attention and distraction processes. These ERP findings of nicotine-augmented early attentional processing add support to the contention that nicotine may be be used by smokers as a “pharmacological tool” for tuning cognitive functions relating to the automatic and controlled aspects of sensory input detection and selection.

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.

Effects of nicotine on visuospatial attentional orienting in non-smokers.

Nicotine is a highly addictive substance, suggested to be in part due to its cognitive enhancing effects in the attentional domain. Improvements in stimulus selection with nicotine have been reported but its effects on visual-spatial selective attention are unclear. This study utilized event-related potentials (ERPs) to examine the acute effects of nicotine on selective attention in non-smokers performing a Posner-type visuo-spatial task. The attentional processing of visual-spatial locations is reflected in the P1 ERP component, which represents earlier stages of visual analysis. 24 non-smokers received nicotine gum (6 mg) in a randomized, double-blind, placebo-controlled, repeated measures design. Behavioral performance and ERPs were assessed in response to target locations preceded by valid, invalid and neutral cues. Nicotine did not affect behavioral performance indices. P1 amplitudes were greater in valid and neutral cue trials compared to invalid cue trials and acute nicotine administration (vs. placebo) was found to increase P1 amplitudes in the right hemisphere, particularly in valid cue trials. In addition, in high symptomatic subjects (as indexed by greater increases in heart rate post-administration), nicotine (vs. placebo) produced greater P1 amplitudes in valid cue trials. The study concludes that nicotine enhanced visuospatial selective attention with regards to early visual encoding and analysis. These results demonstrate support in general for the attentional effects of nicotine and nicotinic agonists and they specifically extend these effects to include orienting of visual-spatial attention.

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.

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.

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.

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.